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The mechanisms governing how the hippocampus selects neurons to exhibit place fields are not well understood. A default assumption in some previous studies was the uniform random draw with replacement (URDWR) model, which, theoretically, maximizes spatial "pattern separation", and predicts a Poisson distribution of the numbers of place fields expressed by a given cell per unit area. The actual distribution of mean firing rates exhibited by a population of hippocampal neurons, however, is approximately exponential or log-normal in a given environment and these rates are somewhat correlated across multiple places, at least under some conditions. The advantage of neural activity-dependent immediate-early gene (IEG) analysis, as a proxy for electrophysiological recording, is the ability to obtain much larger samples of cells, even those whose activity is so sparse that they are overlooked in recording studies. Thus, a more accurate representation of the activation statistics can potentially be achieved. Some previous IEG studies that examined behavior-driven IEG expression in CA1 appear to support URDWR. There was, however, in some of the same studies, an under-recruitment of dentate gyrus granule cells, indicating a highly skewed excitability distribution, which is inconsistent with URDWR. Although it was suggested that this skewness might be related to increased excitability of recently generated granule cells, we show here that CA1, CA3, and subiculum also exhibit cumulative under-recruitment of neurons. Thus, a highly skewed excitability distribution is a general principle common to all major hippocampal subfields. Finally, a more detailed analysis of the frequency distributions of IEG intranuclear transcription foci suggests that a large fraction of hippocampal neurons is virtually silent, even during sleep. Whether the skewing of the excitability distribution is cell-intrinsic or a network phenomenon, and the degree to which this excitability is fixed or possibly time-varying are open questions for future studies. © 2016 Wiley Periodicals, Inc.

Objective. To assess the characteristics and correlates of sleep problems in patients with lifetime posttraumatic stress disorder and ongoing sleep disturbance not due to obstructive sleep apnea or other diagnosed sleep disorders. Sample. Twenty-six veterans receiving psychiatric care at the Minneapolis Veterans Affairs Medical Center in Minneapolis, Minnesota. Data collection instruments. The Pittsburgh Sleep Quality Index, sleep logs, and actigraph along with three symptom ratings scales--posttraumatic checklist, clinicianadministered posttraumatic stress disorder scale, and Beck Depression Inventory--were used. Results. Univariate analysis associated three symptom complexes with poorer sleep quality: posttraumatic avoidance, posttraumatic hypervigilance, and depressive symptoms. Borderline trends also existed between worse sleep quality and more severe clinician-rated posttraumatic stress, more self-reported awakenings from sleep, and greater actigraphydetermined sleep duration. Using linear regression, only posttraumatic hypervigilance symptoms were associated with sleep quality. Conclusion. Sleep quality among posttraumatic stress disorder patients in active treatment is worse in direct relation to more severe posttraumatic hypervigilance symptoms. [ABSTRACT FROM AUTHOR]

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APP NL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APP NL-G-F/NL-G-F mice given multi-domain cognitive training compared to APP NL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APP NL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APP NL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease., (© 2023. The Author(s).)

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made using N-methyl-D-aspartate (NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67% to 97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, do not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This study investigated the impact of familial Alzheimer's disease (AD)-linked amyloid precursor protein (App) mutations on hippocampal CA1 neuronal activity and function at an early disease stage in App NL-G-F/NL-G-F × Thy1-GCaMP6s +/- (A-TG) mice using calcium imaging. Longitudinal assessment of spatial behavior at 12 and 18 months of age identified an early disease stage at 12 months when there was significant amyloid beta pathology with mild behavioral deficits. Hippocampal CA1 neuronal activity and event-related encoding of distance and time were therefore assessed at 12 months of age in several configurations of an air-induced running task to assess the dynamics of cellular activity. Neurons in A-TG mice displayed diminished (weaker) and more frequent (hyperactive) neuronal firing that was more pronounced during movement compared to immobility. Responsive neurons showed configuration-specific deficits in distance and time encoding with impairment in adapting their responses to changing configurations. These results suggest that at an early stage of AD in the absence of full-blown behavioral deficits, weak-hyperactive neuronal activity may induce impairments in sensory perception of changing environments., Competing Interests: Disclosure statement The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APP NL-G-F mice were exposed to long-term voluntary exercise., Methods: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells., Results: The results showed that APP NL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APP NL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APP NL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise., Conclusion: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD., (© 2022. The Author(s).)

Alzheimer's disease (AD) is characterized by the prion-like propagation of amyloid-β (Aβ). However, the role of Aβ in cognitive impairment is still unclear. To determine the causal role of Aβ in AD, we intracerebrally seeded the entorhinal cortex of a 2-month-old App NL - G - F mouse model with an Aβ peptide derived from patients who died from rapidly progressing AD. When the mice were 3 months of age or 1 month following seeding, spatial learning and memory were tested using the Morris water task. Immunohistochemical labeling showed seeding with the Aβ was found accelerate Aβ plaque deposition and microgliosis in the App NL - G - F mice, but this was dependent on the presence of the knocked-in genes. However, we found no correlation between pathology and spatial performance. The results of the present study show the seeding effects in the App NL - G - F knock-in model, and how these are dependent on the presence of a humanized App gene. But these pathological changes were not initially causal in memory impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lacoursiere, Safar, Westaway, Mohajerani and Sutherland.)

Documenting a mouse's "real world" behavior in the "small world" of a laboratory cage with continuous video recordings offers insights into phenotypical expression of mouse genotypes, development and aging, and neurological disease. Nevertheless, there are challenges in the design of a small world, the behavior selected for analysis, and the form of the analysis used. Here we offer insights into small world analyses by describing how acute behavioral procedures can guide continuous behavioral methodology. We show how algorithms can identify behavioral acts including walking and rearing, circadian patterns of action including sleep duration and waking activity, and the organization of patterns of movement into home base activity and excursions, and how they are altered with aging. We additionally describe how specific tests can be incorporated within a mouse's living arrangement. We emphasize how machine learning can condense and organize continuous activity that extends over extended periods of time., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Evidence from genetic, behavioural, anatomical, and physiological study suggests that the hippocampus functionally differs across its longitudinal (dorsoventral or septotemporal) axis. Although, how to best characterize functional and representational differences in the hippocampus across its long axis remains unclear. While some suggest that the hippocampus can be divided into dorsal and ventral subregions that support distinct cognitive functions, others posit that these regions vary in their granularity of representation, wherein spatial-temporal resolution decreases in the ventral (temporal) direction. Importantly, the cognitive and granular hypotheses also make distinct predictions on cellular recruitment dynamics under conditions when animals perform tasks with qualitatively different cognitive-behavioural demands. One interpretation of the cognitive function account implies that dorsal and ventral cellular recruitment differs depending on relevant behavioural demands, while the granularity account suggests similar recruitment dynamics regardless of the nature of the task performed. Here, we quantified cellular recruitment with the immediate early gene (IEG) Arc across the entire longitudinal CA1 axis in female and male rats performing spatial- and fear-guided memory tasks. Our results show that recruitment is greater in dorsal than ventral CA1 regardless of task or sex, and thus support a granular view of hippocampal function across the long axis. We further discuss how future experiments might determine the relative contributions of cognitive function and granularity of representation to neuronal activity dynamics in hippocampal circuits., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Damage to the hippocampus (HPC) typically causes retrograde amnesia for contextual fear conditioning. Repeating the conditioning over several sessions, however, can eliminate the retrograde amnesic effects. This form of reinstatement thus permits modifications to networks that can support context memory retrieval in the absence of the HPC. The present study aims to identify cortical regions that support the nonHPC context memory. Specifically, the contribution of the perirhinal cortex (PRH) and the anterior cingulate cortex (ACC) were examined because of their established importance to context memory. The findings show that context memories established through distributed reinstatement survive damage limited only to the HPC, PRH, or ACC. Combined lesions of the HPC and PRH, as well as the HPC and ACC, caused retrograde amnesia, suggesting that network modifications in the PRH and ACC enable context fear memories to become resistant to HPC damage., (© 2021 Shepherd et al.; Published by Cold Spring Harbor Laboratory Press.)

We test the hypothesis that the stability and precision of context and visual discrimination memories depend on interactions between the hippocampus (HPC) and other memory storage networks. In four experiments we tested the properties of memories acquired in the absence of the HPC. Long-Evans male rats were exclusively used in all experiments. Experiment 1 evaluated acquisition and retention of context fear memories in rats with prior partial or complete HPC damage. Confirming an earlier report (Zelikowsky et al., 2012) a very small but statistically reliable slowing in a single session of context fear conditioning was found after HPC damage. In contrast, retention of context fear memory was normal after HPC damage up to 30 d after learning. In experiment 2, we found that discrimination between a context paired with foot shocks and a different context never paired with foot shock was retained normally for 15 d. In experiment 3, we replicated the finding of intact context discrimination for at least 15 d in rats who display a significant impairment in acquisition of place learning in the Morris water task (MWT). In final experiment using an appetitive object discrimination task, we showed normal retention of the discrimination for at least 30 d after training in rats with complete HPC damage. These finding score against the idea that non HPC memory storage requires a period of interaction with HPC to establish a stable, precise memory. SIGNIFICANCE STATEMENT Contrary to expectations from systems memory consolidation, we find that in the absence of a functional hippocampus (HPC) context and visual memories are formed rapidly and exhibit normal persistence and precision. The findings suggest that the HPC is not obligatory for these features of long-term memories., (Copyright © 2021 the authors.)

Multiple trace theory (Nadel & Moscovitch, Current Opinion in Neurobiology, 1997, 7, 217-227) has proven to be one of the most novel and influential recent memory theories, and played an essential role in shifting perspective on systems-level memory consolidation. Here, we briefly review its impact and testable predictions and focus our discussion primarily on nonhuman animal experiments. Perhaps, the most often supported claim is that episodic memory tasks should exhibit comparable severity of retrograde amnesia (RA) for recent and remote memories after extensive damage to the hippocampus (HPC). By contrast, there appears to be little or no experimental support for other core predictions, such as temporally limited RA after extensive HPC damage in semantic memory tasks, temporally limited RA for episodic memories after partial HPC damage, or the existence of storage of multiple HPC traces with repeated reactivations. Despite these shortcomings, it continues to be a highly cited HPC memory theory., (© 2019 Wiley Periodicals, Inc.)

Alzheimer's disease (AD) is characterized neuropathologically by progressive neurodegeneration and by the presence of amyloid plaques and neurofibrillary tangles. These plaques and tangles are composed, respectively, of amyloid-beta (Aβ) and tau proteins. While long recognized as hallmarks of AD, it remains unclear what causes the formation of these insoluble deposits. One theory holds that prion-like templated misfolding of Aβ and tau induces these proteins to form pathological aggregates, and propagation of this misfolding causes the stereotyped progression of pathology commonly seen in AD. Supporting this theory, numerous studies have been conducted in which aggregated Aβ, tau, or α-synuclein is injected intracerebrally into pathology-free host animals, resulting in robust formation of pathology. Here, we review this literature, focusing on in vivo intracerebral seeding of Aβ and tau in mice. We compare the results of these experiments to what is known about the seeding and spread of α-synuclein pathology, and we discuss how this research informs our understanding of the factors underlying the onset, progression, and outcomes of proteinaceous pathologies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Behavioural responses to stress occur in an environment-dependent manner. Complex environments require flexible behavioural coping strategies and chronic stress usually generates psychomotor inhibition. Here, we examine if short-term stress also exerts an inhibitory effect on novelty-seeking, exploratory behaviours. Rats underwent acute restraint stress or were left undisturbed, and their neuroendocrine and behavioural responses were assessed at short- and long-term time points. Animals were individually tested in the open field task (OFT) and the corridor field task (CFT) with and without a central object for free exploration and novelty seeking behaviour. Stress-related psychomotor alterations were measured by path speed, path length, number of stops and thigmotaxis in both tasks. Short-term stress activated the hypothalamic-pituitary-adrenal axis causing elevated plasma corticosterone levels. Stress also impacted psychomotor functions in terms of motivational changes (higher speed and longer path) only in the central-object variations of the OFT and CFT. Moreover, stress-induced emotional alterations were manifested by a higher number of stops and thigmotactic behaviour only in the central-object condition. These findings suggest that environmental landmarks determine the type and direction of exploratory behaviour under transient stress., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Previous work has shown that the dorsal hippocampus has greater activity than ventral regions during place navigation. Exposure to a novel context has also been found to increase hippocampal activation, possibly due to increased spatial demands. However, activation patterns in dorsal and ventral regions have not been investigated in the Morris water task (MWT), which remains the most popular assay of place memory in rodents. We measured activity in a large population of neurons across the CA1 dorsal-ventral axis by estimating nuclear Arc mRNA with stereologic systematic-random sampling procedures following changes to goal location or spatial context in the MWT in rats. Following changes to goal location or spatial context in the MWT, we did not find an effect on Arc mRNA expression in CA1. However, Arc expression was greater in the dorsal compared to the ventral aspect of CA1 during task performance. Several views might account for these observed differences in dorsal-ventral Arc mRNA expression, including task parameters or the granularity of representation that differs along the dorsal-ventral hippocampal axis. Future work should determine the effects of task differences and required memory precision in relation to dorsal-ventral hippocampal neuronal activity., (© 2019 Wiley Periodicals, Inc.)

In the current research on measuring complex behaviours/phenotyping in rodents, most of the experimental design requires the experimenter to remove the animal from its home-cage environment and place it in an unfamiliar apparatus (novel environment). This interaction may influence behaviour, general well-being, and the metabolism of the animal, affecting the phenotypic outcome even if the data collection method is automated. Most of the commercially available solutions for home-cage monitoring are expensive and usually lack the flexibility to be incorporated with existing home-cages. Here we present a low-cost solution for monitoring home-cage behaviour of rodents that can be easily incorporated to practically any available rodent home-cage. To demonstrate the use of our system, we reliably predict the sleep/wake state of mice in their home-cage using only video. We validate these results using hippocampal local field potential (LFP) and electromyography (EMG) data. Our approach provides a low-cost flexible methodology for high-throughput studies of sleep, circadian rhythm and rodent behaviour with minimal experimenter interference., Competing Interests: Some of the authors (EBC, MHM, and RJS) have a financial interest in the company “NeuroCage Systems Inc.” that is developing a product “Homecage Monitoring System” whose initial design was inspired by the results presented in this work. Some of the authors (SS, EBC, MHM, and RJS) have a patent application that includes some of the functionality presented in this work. Pending patent for SYSTEMS AND METHODS OF HOMECAGE MONITORING; patent application # 62/857,879 (US) and 3,045,478 (Canada). There are no further products in development, or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Explanations of memory-guided navigation in rodents typically suggest that cue- and place-based navigations are independent aspects of behavior and neurobiology. The results of many experiments show that hippocampal damage causes both anterograde and retrograde amnesia (AA; RA) for place memory, but only RA for cue memory. In the present experiments, we used a concurrent cue-place water task (CWT) to study the effects of hippocampal damage before or after training on cue- and place-guided navigation, and how cue and place memory interact in damaged and control rats. We found that damaging the hippocampus before training caused a delay in the expression of cue-place navigation strategies relative to intact control animals; surprisingly, place navigation strategies emerged following pre-training hippocampal damage. With additional training, both control and damaged rats used local cues to navigate in the CWT. Damaged animals also show minor impairments in latency to navigate to the correct cue following a cue contingency reversal. By contrast to these anterograde effects, damage made after training causes RA for cue choice accuracy and latency to navigate to the correct cue. In addition, the extent of hippocampal damage predicted impairments in choice accuracy when lesions were made after training. These data extend previous work on the role of the hippocampus in cue and place memory-guided navigation, and show that the hippocampus plays an important role in both aspects of memory and navigation when present during the learning experience., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Saito et al developed a novel amyloid precursor protein (APP) knock-in mouse model (APP NL-G-F ) for Alzheimer's disease (AD) to overcome the problem of overexpression of APP in available transgenic mouse models. However, this new mouse model for AD is not fully characterized age-dependently with respect to behavioral and biochemical changes. Therefore, in the present study, we performed an age-dependent behavioral and biochemical characterization of this newly developed mouse model. Here, we used 3-, 6-, 9-, and 12-month-old APP NL-G-F and C57BL/6J mice. We used a separate cohort of animals at each age point. Morris water maze, object recognition, and fear-conditioning tests were used for the assessment of learning and memory functions and open-field test to measure the general locomotor activity of mice. After each testing point, we perfused the mice and collected the brain for immunostaining. We performed the immunostaining for amyloid burden (4G8), glial fibrillary acidic protein, choline acetyltransferase, and tyrosine hydroxylase. The results of the present study indicate that APP NL-G-F mice showed age-dependent memory impairments with maximum impairment at the age of 12 months. These mice showed memory impairment in Morris water maze and fear conditioning tests when they were 6 months old, whereas, in object recognition test, memory deficit was found in 9-month-old mice. APP NL-G-F mice age dependently showed an increase in amyloid load in different brain regions. However, no amyloid pathology was found in 3-month-old APP NL-G-F mice. Choline acetyltransferase neurons in medial septum-diagonal band complex and tyrosine hydroxylase neurons in locus coeruleus were decreased significantly in APP NL-G-F mice. This mouse model also indicated an age-dependent increase in glial fibrillary acidic protein load. It can be concluded from the results that the APP NL-G-F mouse model may be used to explore the Aβ hypothesis, molecular, and cellular mechanisms involved in AD pathology and to screen the therapeutic potential compounds for the treatment of AD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Multiple neural systems contribute to choice adaptation following reinforcement. Recent evidence suggests that the lateral habenula (LHb) plays a key role in such adaptations, particularly when reinforcements are worse than expected. Here, we investigated the effects of bilateral LHb lesions on responding in a binary choice task with no discriminatory cues. LHb lesions in rats decreased win-stay responses but surprisingly left lose-shift responses intact. This same dissociated effect was also observed after systemic administration of d-amphetamine in a separate cohort of animals. These results suggest that at least some behavioural responses triggered by reward omission do not depend on an intact LHb., (Copyright © 2018. Published by Elsevier B.V.)

The activity of CA1 neurons in the rodent hippocampus represents multiple aspects of learning episodes, including cue and place information. Previous reports on cue and place representation in CA1 have examined activity in single neurons and population recordings during free exploration of an environment or when actions are directed to either cue or place aspects of memory tasks. To better understand cue and place memory representation in CA1, and how these interact during goal-directed navigation, we investigated population activity in CA1 during memory encoding and retrieval in a novel water task with two visibly distinct platforms, using mRNA for immediate early genes Arc and Homer1a as markers of neural activity. After training, relocating cues to new places induces an extensive, perhaps global, remapping of the memory code that is accompanied by altered navigation and rapid learning of new cue-place information. In addition, we have found a significant relationship between the extent of reactivation and overall cue choice accuracy. These findings demonstrate an important relationship between population remapping in CA1 and memory-guided behavior., (© 2018 Wiley Periodicals, Inc.)

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre- or post-training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non-HPC system that can acquire long-term memories that support context fear discrimination. Post-training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long-term memory., (© 2017 Wiley Periodicals, Inc.)

Evidence from clinical and animal research highlights the role of the hippocampus in long-term memory (LTM). Decades of experimental work have produced numerous theoretical accounts of the hippocampus in LTM, and each suggests that hippocampal disruption produces amnesia for specific categories of memory. These accounts also imply that hippocampal disruption before or soon after a learning episode should have equivalent amnestic effects. Recent evidence from lesion and inactivation experiments in rodents illustrates that hippocampal disruption after a learning episode causes memory impairment in a wider range of memory tasks than if the same disruption occurs before learning. Although this finding supports that multiple circuits can acquire and retrieve similar information, it also suggests they do not do so independently. In addition, damage after learning produces amnesia for simple elements of a task as well as complex, conjunctive features. Here we develop an explanation for why anterograde and retrograde hippocampal effects differ. This explanation, the heterarchic reinstatement view, also generates novel predictions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Anatomical and electrophysiological evidence suggest the dorsolateral entorhinal cortex (DLEC) is involved in processing spatial information, but there is currently no consensus on whether its functions are necessary for normal spatial learning and memory. The present study examined the effects of excitotoxic lesions of the DLEC on retrograde and anterograde memory on two tests of allocentric spatial learning: a hidden fixed-platform watermaze task, and a novelty-preference-based dry-maze test. Deficits were observed on both tests when training occurred prior to but not following n-methyl d-aspartate (NMDA) lesions of DLEC, suggesting retrograde memory impairment in the absence of anterograde impairments for the same information. The retrograde memory impairments were temporally-graded; rats that received DLEC lesions 1-3 days following training displayed deficits, while those that received lesions 7-10 days following training performed like a control group that received sham surgery. The deficits were not attenuated by co-infusion of tetrodotoxin, suggesting they are not due to disruption of neural processing in structures efferent to the DLEC, such as the hippocampus. The present findings provide evidence that the DLEC is involved in the consolidation of allocentric spatial information., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The standard model of systems consolidation holds that the hippocampus (HPC) is involved only in the initial storage and retrieval of a memory. With time hippocampal-neocortical interactions slowly strengthen the neocortical memory, ultimately enabling retrieval of the memory without the HPC. Key support for this idea comes from experiments measuring memory recall in the socially-transmitted food preference (STFP) task in rats. HPC damage within a day or two of STFP learning can abolish recall, but similar damage five or more days after learning has no effect. We hypothesize that disruption of cellular consolidation outside the HPC could contribute to the amnesia with recent memories, perhaps playing a more important role than the loss of HPC. This view predicts that intraHPC infusion of Tetrodotoxin (TTX), which can block conduction of action potentials from the lesion sites, will block the retrograde amnesia in the STFP task. Here we confirm the previously reported retrograde amnesia with neurotoxic HPC damage within the first day after learning, but show that co-administration of TTX with the neurotoxin blocks the retrograde amnesia despite very extensive HPC damage. These results indicate that HPC damage disrupts cellular consolidation of the recent memory elsewhere; STFP memory may not ever depend on the HPC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Structural learning theory suggests that experiencing motor task variation enables the central nervous system to extract general rules regarding tasks with a similar structure - rules that can subsequently be applied to novel situations. Complex minimally invasive surgery (MIS) requires different port sites, but switching ports alters the limb movements required to produce the same endpoint control of the surgical instrument. The purpose of the present study was to determine if structural learning theory can be applied to MIS to inform training methods., Methods: A tablet laptop running bespoke software was placed within a laparoscopic box trainer and connected to a monitor situated at eye level. Participants (right-handed, non-surgeons, mean age = 23.2 years) used a standard laparoscopic grasper to move between locations on the screen. There were two training groups: the M group (n = 10) who trained using multiple port sites, and the S group (n = 10) who trained using a single port site. A novel port site was used as a test of generalization. Performance metrics were a composite of speed and accuracy (SACF) and normalized jerk (NJ; a measure of movement 'smoothness')., Results: The M group showed a statistically significant performance advantage over the S group at test, as indexed by improved SACF (p < 0.05) and NJ (p < 0.05)., Conclusions: This study has demonstrated the potential benefits of incorporating a structural learning approach within MIS training. This may have practical applications when training junior surgeons and developing surgical simulation devices.

Temporary cellular inactivation is a useful and increasingly popular approach in examining brain function. In general the methods allow for fast-acting manipulations that have the advantage of being reversible. However, there is significant variation in detailed procedures across experiments and most authors show very little evidence about the extent or duration of inactivation. Here we investigate a commonly used method of temporarily inactivating the hippocampus in rats. Using immediate early gene activation after electroconvulsive shock we measure the extent of inactivation using different lengths of infusion needles and one vs. two bilateral infusion sites. Our methods allowed us to uncover some possible confounding factors. We suggest specific variations in the procedures which decrease or eliminate these problems. We also investigate the properties of the sodium channel blocker ropivacaine and recommend this drug based on its functional profile and established low level of toxicity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

There are still basic uncertainties concerning the role of the hippocampus (HPC) in maintaining long-term context memories. All experiments examining the effects of extensive HPC damage on context memory for a single learning episode find that damage soon after learning results in robust retrograde amnesia. Some experiments find that if the learning-to-damage interval is extended, remote context memories are spared. In contrast, other experiments fail to find spared remote context memory. One possible explanation for inconsistency might be the potency of the context memory conditioning procedure, as the experiments showing spared remote memory used a greater number of context-shock pairings, likely creating a stronger context fear memory. We designed an experiment to directly test the question: does increasing the number of context-shock pairings result in sparing of remote context memory after HPC damage? Six independent groups of rats received either 3 or 12 context-shock pairings during a single conditioning session and then either received extensive HPC damage or Control surgery at 1-week, 2-months, or 4-months after conditioning. 10 days after surgery rats were tested for memory of the shock context. Consistent with all relevant studies, HPC damage at the shortest training-surgery interval produced robust retrograde amnesia for both 3- and 12-shock groups whereas the Control rats expressed significantly high levels of memory. At the longer training-surgery interval, HPC damage produced similarly robust retrograde amnesia in the rats in both the 3- and 12-shock groups. These results clearly demonstrate that increasing the number of context-shock pairings within a single learning session does not change the dependence of the memory on the HPC. Current evidence from our group on retrograde amnesia has now shown that partial damage, dorsal vs. ventral damage, discrete cue+context conditioning, time after training, and number of context-shock pairings do not affect HPC dependence of context fear memories. When taken together, the evidence strongly supports a permanent role of the HPC in context memory., (Copyright © 2013 Elsevier Inc. All rights reserved.)

There are still uncertainties about the role of the hippocampus (HPC) in memory consolidation. One theory, systems consolidation, states that the HPC is required for the initial storage of certain memories that subsequently become established in non-HPC networks through a lengthy process, involving an interaction with the HPC. A similar process may underlie the ability of multiple, distributed learning episodes of contextual fear conditioning to create a HPC-independent context fear memory, in a memory task that does not undergo systems consolidation with the mere passage of time [5]. The current study examined whether post-learning HPC activity is necessary to establish these HPC-independent context memories through distributed learning episodes. Rats received either three or six context conditioning sessions over the course of three days. The HPC-dependence of context memories was assessed using multisite, temporary inactivation of the HPC using ropivacaine during retention testing. We established that six conditioning sessions, but not three, created a memory that could be retrieved while the HPC was inactive. To directly test our hypothesis, HPC was inactivated after half of the six context-shock pairings in an independent group of rats. The rats were then tested for retention of context fear in the absence of HPC activity. Post-learning inactivation of the HPC did not affect the establishment of a HPC-independent context memory. These results favor the idea that at least one memory system outside the HPC can acquire context memories independently., (Copyright © 2012. Published by Elsevier B.V.)

This study investigated how both sex and individual differences in a mental rotation test (MRT) influence performance on working memory (WM). To identify the neural substrate supporting these differences, brain electrical activity was measured using the event-related potential technique. No significant sex differences were observed in a test of verbal WM, however males were significantly faster than females to respond to probe stimuli in a test of spatial WM. This difference was no longer significant after controlling for differences in MRT score, suggesting that rotational ability mediates performance in the spatial memory task for both sexes. A posterior P300 was observed in both tasks as participants encoded information into memory, however the amplitude of the P300 correlated with RT in the spatial task but not in the verbal task. Individual differences in the MRT also correlated with RT and with the amplitude of the P300, but again only in the spatial task. After splitting the analysis by sex, partial correlations controlling for MRT revealed that for males, individual differences in rotational ability completely mediated the correlation between the P300 and RT in the spatial task. This mediating effect was not observed for the female participants. The results therefore suggest a relatively stronger association in males between innate mental rotational ability, spatial memory performance, and brain electrophysiological processes supporting spatial memory.

The time when an event occurs can become part of autobiographical memories. In brain structures that support such memories, a neural code should exist that represents when or how long ago events occurred. Here we describe a neuronal coding mechanism in hippocampus that can be used to represent the recency of an experience over intervals of hours to days. When the same event is repeated after such time periods, the activity patterns of hippocampal CA1 cell populations progressively differ with increasing temporal distances. Coding for space and context is nonetheless preserved. Compared with CA1, the firing patterns of hippocampal CA3 cell populations are highly reproducible, irrespective of the time interval, and thus provide a stable memory code over time. Therefore, the neuronal activity patterns in CA1 but not CA3 include a code that can be used to distinguish between time intervals on an extended scale, consistent with behavioral studies showing that the CA1 area is selectively required for temporal coding over such periods.

Group-based exposure therapy (GBET) is an intensive group treatment that targets posttraumatic stress disorder (PTSD) symptoms through repeated imaginal and in vivo exposure. The purpose of the present study was to assess the feasibility and acceptability of a modified 12-week course of GBET (modified from the standard 16 weeks) and to examine its effectiveness in reducing veterans' PTSD symptoms. Participants were 10 male Operation Iraqi Freedom and Vietnam-era veterans recruited from a PTSD specialty clinic at a large Veterans Affairs Medical Center. All participants were retained and demonstrated clinically significant reductions in PTSD symptoms (η(2) = .84-.87) comparable to the standard protocol. The findings from this small sample indicate that the abbreviated 12-week GBET protocol is a potentially effective treatment for PTSD., (Copyright © 2012 International Society for Traumatic Stress Studies.)

Stress has been linked to structural and functional outcomes after stroke. Moreover, the striatum, both dorsal and ventral, is a vital regulator of stress perception and associated physiological responses. This study investigates potential synergistic effects of focal stroke in the ventrolateral striatum and restraint stress on motor and spatial performance. Adult male Long-Evans rats were pre-trained in a skilled reaching task and randomly assigned to sham, stroke-only, stress-only and stroke+stress conditions. Ventrolateral striatal focal ischemia was induced by endothelin-1 (ET-1) infusion. Rats in stress-only and stroke+stress groups received 21 days of mild restraint stress after stroke. All rats were tested in the skilled reaching task and the ziggurat task (ZT) for post-stroke motor and spatial performance. There was no effect of ventrolateral striatal ischemia or stress alone on motor and spatial performance. Notably, stroke and stress interacted synergistically to reduce reaching success and to disrupt qualitative aspects of movement performance in the absence of histological differences in lesion size. Thus, stress can precipitate behavioural deficits after focal ischemia even in the absence of significant functional deficits on its own. These results emphasize the importance of prevention programmes to control post-stroke levels of stress in clinical populations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The hippocampus maintains the remarkable ability to generate new neurons throughout the lifespan. Progenitor cells in the subgranular zone give rise mainly to granule cells that migrate to the granule cell layer and become mature, functionally integrated neurons. Numerous factors are capable of regulating the proliferation and survival of new neurons in the adult hippocampus. Corticosterone is one of the most potent factors. Stress results in a significant decrease in the number of dividing cells and exogenous corticosterone administration produces a similar result. Conversely, removal of circulating glucocorticoids via adrenalectomy has been shown to dramatically increase cell proliferation. However, no studies have examined the long-term effects of adrenalectomy on cell proliferation in the hippocampus. In addition to increasing cell proliferation in the hippocampus, chronic adrenalectomy induces ongoing cell death in the dentate gyrus. In order to determine the time course of cell proliferation and cell death in the dentate gyrus following corticosterone removal we examined the dentate gyrus of rats at several time points following adrenalectomy. We analyzed the number of proliferating cells based on Ki67 labeling and visualized cell death using Fluoro-Jade B. Here we show that although cell proliferation is initially enhanced by adrenalectomy, but the increase is transient; it is no longer apparent by 4 weeks after adrenalectomy. Furthermore, we demonstrate that cell death is pronounced by 3 days after adrenalectomy and continues for at least 23 weeks., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Context memories normally depend on the hippocampus (HPC) but, in the absence of the HPC, other memory systems are capable of acquiring and supporting these memories. This suggests that the HPC can interfere with other systems during memory acquisition. Here we ask whether the HPC can also interfere with the retrieval of a context memory that was independently acquired by a non-HPC system. Specifically, we assess whether the HPC can impair the retrieval of a contextual fear-conditioning memory that was acquired while the HPC was temporarily inactive. Rats were infused with the γ-aminobutyric acid (GABA)(A) receptor agonist muscimol in the dorsal and ventral HPC either before acquisition, retrieval, or prior to both acquisition and retrieval, consistent with the effects of permanent HPC lesions on contextual fear conditioning, if the HPC was inactive at the time of acquisition and retention memory was intact. Thus, non-HPC systems acquired and supported this memory in absence of the HPC. However, if the HPC was inactive during acquisition but active thereafter, rats displayed severe deficits during the retention test. Moreover, when the same rats received a second retention test but with the HPC inactive at this time, the memory was recovered, suggesting that removal of a form of interference allowed the memory to be expressed. Combined, these findings imply that the HPC competes and/or interferes with retrieval of a long-term memory that was established in non-HPC systems., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

The nature of stress-related cognitive changes is still a matter of debate. Stress is often considered to be deleterious to cognitive function, despite many instances in which beneficial effects are evident in neural structure and cognition. Moreover, in some neuropathological conditions such as focal ischemia, stress exaggerates loss of cognitive function. The present experiments set out to investigate the effects of repeated restraint stress on spatial cognition in rats, and on recovery from a focal stroke induced by injection of endothelin-1 (ET-1) into the hippocampus (HPC). We did not observe a deleterious effect of stress on performance in the Morris water task (MWT). The HPC focal stroke induced by ET-1 produced lasting spatial learning impairments. Importantly, rats in the HPC stroke+stress group exhibited superior performance in the MWT compared with the HPC stroke-only group. No between-group structural difference was observed related to stress. These findings confirm that corticosterone-related experiences may be key factors influencing cognitive performance after HPC focal ischemic stroke., (2010 Elsevier Inc. All rights reserved.)

Exposure to combat experiences is associated with increased risk of developing Post Traumatic Stress Disorder. Prolonged exposure therapy and cognitive processing therapy have garnered a significant amount of empirical support for PTSD treatment; however, they are not universally effective with some patients continuing to struggle with residual PTSD symptoms. Heart rate variability (HRV) is a measure of the autonomic nervous system functioning and reflects an individual's ability to adaptively cope with stress. A pilot study was undertaken to determine if veterans with PTSD (as measured by the Clinician-Administered PTSD Scale and the PTSD Checklist) would show significantly different HRV prior to an intervention at baseline compared to controls; specifically, to determine whether the HRV among veterans with PTSD is more depressed than that among veterans without PTSD. The study also aimed at assessing the feasibility, acceptability, and potential efficacy of providing HRV biofeedback as a treatment for PTSD. The findings suggest that implementing an HRV biofeedback as a treatment for PTSD is effective, feasible, and acceptable for veterans. Veterans with combat-related PTSD displayed significantly depressed HRV as compared to subjects without PTSD. When the veterans with PTSD were randomly assigned to receive either HRV biofeedback plus treatment as usual (TAU) or just TAU, the results indicated that HRV biofeedback significantly increased the HRV while reducing symptoms of PTSD. However, the TAU had no significant effect on either HRV or symptom reduction. A larger randomized control trial to validate these findings appears warranted.

Stress is one of the most important variables to determine recovery following stroke. We have previously reported that post-stroke exposure to either stress or corticosterone (CORT) alleviates hippocampal ischemic outcome. The present experiment expands previous findings by investigating the influence of exposure to stress prior to ischemic event. Rats received either daily restraint stress (1h/day; 16 consecutive days) or CORT (0.5mg/kg; 16 consecutive days) prior to focal ischemic stroke in the hippocampus induced by bilateral injection of endothelin-1 (ET-1). All experimental groups were then tested in the ziggurat task, a new task for spatial cognition. The stress+stroke group showed significant deficits in both hippocampal structure and function. No deleterious effect of pre-stroke exposure to CORT was found in the CORT+stroke group. Our results indicate that a history of chronic stress sensitizes hippocampal cells to the damaging consequences of focal ischemia. The opposing effects of CORT-related experiences in this study not only reflect the diversity of glucocorticoid actions in the stress response, but also provide evidence that elevated CORT in the absence of emotional disturbance is not sufficient to produce hippocampal deficit., (Copyright © 2011 Elsevier Inc. All rights reserved.)