Lipopolysaccharide exposure in a rat sepsis model results in hippocampal amyloid-ß plaque and phosphorylated tau deposition and corresponding behavioral deficits.

Sepsis is a severe systemic inflammatory response to infection associated with acute and chronic neurocognitive consequences, including an increased risk of later-life dementia. In a lipopolysaccharide-induced rat sepsis model, we have demonstrated neuroinflammation, cortical amyloid-beta plaque deposition, and increased whole brain levels of phosphorylated tau. Hippocampal abnormalities, particularly those of the dentate gyrus, are seen in Alzheimer's disease and age-related memory loss. The focus of this study was to determine whether Aß plaques and phosphorylated tau aggregates occur in the hippocampus as a consequence of lipopolysaccharide administration, and whether behavioral abnormalities related to the hippocampus, particularly the dentate gyrus, can be demonstrated. Male Sprague Dawley rats received an intraperitoneal injection of 10 mg/kg of lipopolysaccharide endotoxin. Control animals received a saline injection. Seven days post injection, Aß plaques and phosphorylated tau in the hippocampus were quantified following immunostaining. Behavioral tests that have previously been shown to result in specific deficits in dentate gyrus-lesioned rats were administered. Lipopolysaccharide treatment results in the deposition of beta amyloid plaques and intracellular phosphorylated tau in the hippocampus, including the dorsal dentate gyrus. Lipopolysaccharide treatment resulted in behavioral deficits attributable to the dorsal dentate gyrus, including episodic-like memory function that primarily involves spatial, contextual, and temporal orientation and integration. Lipopolysaccharide administration results in hippocampal deposition of amyloid-beta plaques and intracellular phosphorylated tau and results in specific behavioral deficits attributable to the dorsal dentate gyrus. These findings, if persistent, could provide a basis for the higher rate of dementia in longitudinal studies of sepsis survivors.

An analysis of dentate gyrus function (an update).

In this review there will be a description of the dentate gyrus (DG) neural circuitry that mediates the operation of a variety of mnemonic processes associated with dorsal and ventral DG function in rats. Dysfunction of the dorsal DG can be shown to mediate mnemonic processing of spatially based information including a) the operation of conjunctive encoding of multiple sensory inputs to determine spatial representations, b) pattern separation based on reducing interference between similar spatial locations and spatial contexts for horizontal distance between objects, vertical distance for height of objects, slope or angle of motor movements, c) importance of spatial context in object recognition and processing of shades of grey associated with the walls of the box d) temporal integration in the creation of remote memory based in part on DG neurogenesis and function of the CA3 subregion of the hippocampus. Dysfunction of the ventral DG can be shown to mediate mnemonic processing of odor and reward value based information including a) pattern separation for odors and reward value, and b) social recognition.

Exploration of the Neurobiological Basis for a Three-System, Multiattribute Model of Memory.

The structure and utilization of memory is central to one's knowledge of the past, interpretation of the present, and prediction of the future. Therefore, the understanding of the structural and process components of memory systems at the psychological and neurobiological level is of paramount importance. There have been a number of attempts to divide learning and memory into multiple memory systems. Schacter and Tulving, Memory systems 1994. MIT Press, Cambridge (1994) have suggested that one needs to define memory systems in terms of the kind of information to be represented, the processes associated with the operation of each system, and the neurobiological substrates, including neural structures and mechanisms, that subserve each system. Furthermore, it is likely that within each system there are multiple forms or subsystems associated with each memory system and there are likely to be multiple processes that define the operation of each system. Finally, there are probably multiple neural structures that form the overall substrate of a memory system.

Unfolding the cognitive map: The role of hippocampal and extra-hippocampal substrates based on a systems analysis of spatial processing.

What has been long absent in understanding the neural circuit that supports spatial processing is a thorough description and rigorous study of the distributed neural networks associated with spatial processing-both in the human as well as in rodents. Most of our understanding regarding the elucidation of a spatial neural circuit has been based on rodents and therefore the present manuscript will concentrate on that literature. There is a trend emerging in research to expand beyond the hippocampus for evaluating spatial memory, but the thrust of the research still focuses on the role of the hippocampus as essential and other neural substrates as performing sub-servient roles to support hippocampus-dependent spatial processing. This review will describe spatial memory in terms of a system model incorporating partially overlapping and interacting event-based, knowledge-based and rule-based memory systems that are composed of different component processes or attributes associated with spatial processing which are mapped onto the corresponding neural substrates and larger networks. In particular, the interactions among brain systems that process spatial information will be emphasized. We propose that these interactions among brain regions are essential for spatial memory.

Adaptation of the Arizona Cognitive Task Battery for use with the Ts65Dn mouse model (Mus musculus) of Down syndrome.

We propose and validate a clear strategy to efficiently and comprehensively characterize neurobehavioral deficits in the Ts65Dn mouse model of Down syndrome. This novel approach uses neurocognitive theory to design and select behavioral tasks that test specific hypotheses concerning the results of Down syndrome. In this article, we model the Arizona Cognitive Task Battery, used to study human populations with Down syndrome, in Ts65Dn mice. We observed specific deficits for spatial memory, impaired long-term memory for visual objects, acquisition and reversal of motor responses, reduced motor dexterity, and impaired adaptive function as measured by nesting and anxiety tasks. The Ts65Dn mice showed intact temporal ordering, novelty detection, and visual object recognition with short delays. These results phenocopy the performance of participants with Down syndrome on the Arizona Cognitive Task Battery. This approach extends the utility of mouse models of Down syndrome by integrating the expertise of clinical neurology and cognitive neuroscience into the mouse behavioral laboratory. Further, by directly emphasizing the reciprocal translation of research between human disease states and the associated mouse models, we demonstrate that it is possible for both groups to mutually inform each other's research to more efficiently generate hypotheses and elucidate treatment strategies. (PsycINFO Database Record

The ventral dentate gyrus mediates pattern separation for reward value.

Rats with ventral dentate gyrus (DG) lesions, sham lesions, and controls were run in a runway for 20 pellets of food. After reaching running speed asymptote, the number of pellets was reduced to 1, 9, or 17 pellets. The purpose of the present experiment was to determine whether the ventral DG subregion of the hippocampus plays a role in pattern separation for reward value. The results indicated that sham lesioned and control rats displayed a graded decrease in runway velocities, supporting a pattern separation process. In contrast, ventral DG lesioned rats continued to maintain runway velocities regardless of the reward-value shifts. The ventral DG lesion results do not appear to be due to hyperactivity but could be based on the idea that the ventral DG is part of a decision-making circuitry to predict goal-relevant reward outcomes. (PsycINFO Database Record

Naloxone injections into CA3 disrupt pattern completion associated with relapse from cocaine seeking.

The goal of the present research was to assess the degree to which a pattern completion process operates in cue-induced relapse to cocaine-seeking behavior. Using a novel cue-preference version of the place preference task, rats were administered cocaine or saline, which resulted in a preference for the cocaine-paired cues. After 21 days of abstinence and prior to the preference test, for one group, PBS or naloxone was injected into the CA3 subregion of the hippocampus and for a second group, saline or naloxone was injected systemically. The results indicated that infusions of naloxone into CA3 or systemic injections produced a marked disruption for one and two cues, but had minimal disruptive effect for three or four cues, suggesting that naloxone injections disrupt CA3 function and trigger a deficit in a pattern completion process. Thus, it appears that cue-based activation of the dorsal CA3 might be a critical trigger via a pattern completion process. Based on additional analyses it appears that there is a disruption primarily for object touches for one cue naloxone injections into the CA3 or systemic injections, but no effect on time (spatial context). © 2016 Wiley Periodicals, Inc.

Dentate gyrus supports slope recognition memory, shades of grey-context pattern separation and recognition memory, and CA3 supports pattern completion for object memory.

In order to examine the role of the dorsal dentate gyrus (dDG) in slope (vertical space) recognition and possible pattern separation, various slope (vertical space) degrees were used in a novel exploratory paradigm to measure novelty detection for changes in slope (vertical space) recognition memory and slope memory pattern separation in Experiment 1. The results of the experiment indicate that control rats displayed a slope recognition memory function with a pattern separation process for slope memory that is dependent upon the magnitude of change in slope between study and test phases. In contrast, the dDG lesioned rats displayed an impairment in slope recognition memory, though because there was no significant interaction between the two groups and slope memory, a reliable pattern separation impairment for slope could not be firmly established in the DG lesioned rats. In Experiment 2, in order to determine whether, the dDG plays a role in shades of grey spatial context recognition and possible pattern separation, shades of grey were used in a novel exploratory paradigm to measure novelty detection for changes in the shades of grey context environment. The results of the experiment indicate that control rats displayed a shades of grey-context pattern separation effect across levels of separation of context (shades of grey). In contrast, the DG lesioned rats displayed a significant interaction between the two groups and levels of shades of grey suggesting impairment in a pattern separation function for levels of shades of grey. In Experiment 3 in order to determine whether the dorsal CA3 (dCA3) plays a role in object pattern completion, a new task requiring less training and using a choice that was based on choosing the correct set of objects on a two-choice discrimination task was used. The results indicated that control rats displayed a pattern completion function based on the availability of one, two, three or four cues. In contrast, the dCA3 lesioned rats displayed a significant interaction between the two groups and the number of available objects suggesting impairment in a pattern completion function for object cues.

Role of the dentate gyrus in mediating object-spatial configuration recognition.

In the present study the effects of dorsal dentate gyrus (dDG) lesions in rats were tested on recognition memory tasks based on the interaction between objects, features of objects, and spatial features. The results indicated that the rats with dDG lesions did not differ from controls in recognition for a change within object feature configuration and object recognition tasks. In contrast, there was a deficit for the dDG lesioned rats relative to controls in recognition for a change within object-spatial feature configuration, complex object-place feature configuration and spatial recognition tasks. It is suggested that the dDG subregion of the hippocampus supports object-place and complex object-place feature information via a conjunctive encoding process.

A computational theory of hippocampal function, and tests of the theory: new developments.

The aims of the paper are to update Rolls' quantitative computational theory of hippocampal function and the predictions it makes about the different subregions (dentate gyrus, CA3 and CA1), and to examine behavioral and electrophysiological data that address the functions of the hippocampus and particularly its subregions. Based on the computational proposal that the dentate gyrus produces sparse representations by competitive learning and via the mossy fiber pathway forces new representations on the CA3 during learning (encoding), it has been shown behaviorally that the dentate gyrus supports spatial pattern separation during learning. Based on the computational proposal that CA3-CA3 autoassociative networks are important for episodic memory, it has been shown behaviorally that the CA3 supports spatial rapid one-trial learning, learning of arbitrary associations where space is a component, pattern completion, spatial short-term memory, and spatial sequence learning by associations formed between successive items. The concept that the CA1 recodes information from CA3 and sets up associatively learned backprojections to neocortex to allow subsequent retrieval of information to neocortex, is consistent with findings on consolidation. Behaviorally, the CA1 is implicated in processing temporal information as shown by investigations requiring temporal order pattern separation and associations across time; and computationally this could involve associations in CA1 between object and timing information that have their origins in the lateral and medial entorhinal cortex respectively. The perforant path input from the entorhinal cortex to DG is implicated in learning, to CA3 in retrieval from CA3, and to CA1 in retrieval after longer time intervals ("intermediate-term memory") and in the temporal sequence memory for objects.

The role of the ventral dentate gyrus in anxiety-based behaviors.

Dorsoventral lesion studies of the hippocampus (HPP) indicate that the dorsal axis is important for spatial processing and the ventral axis is important in anxiety and olfactory processes. There is some evidence that ventral CA3 and ventral CA1 subregions are important for cued retrieval in fear conditioning, which supports a ventral-anxiety relationship. However, the role of the ventral dentate gyrus (DG) in anxiety-based behaviors is less understood. Therefore, we used elevated plus and open field mazes to investigate the role of the ventral DG in the ability to modify behavior in potentially dangerous conditions and to clarify a few previous reports that ventral HPP lesions may induce hyperactivity. Rats with ventral DG lesions spent significantly more time in the open arms of the elevated plus maze and inner zone of the open field test than did controls and rats with dorsal DG lesions. Locomotor measures indicate that all rats traveled at similar rates in enclosed arms, as well as in open arms of the elevated plus maze and all groups traveled at similar rates in the open field test, which indicates that differences in exploration were not likely due to hyperactivity. The present study findings indicate that the ventral DG plays an important role in anxiety-based behaviors, such as preference for safer environments and the ability to modify exploratory behavior when in potentially dangerous environments and that the dorsal DG is not importantly involved in anxiety.

The role of postnatal neurogenesis in supporting remote memory and spatial metric processing.

In this study, we determined the contribution of juvenile neurogenesis to the performance of mice on a remote memory for temporally based association task and in a novelty based spatial pattern separation task. This was accomplished by mating homozygous DNMT1-loxP mice with heterozygous GFAP-Cre mice and comparing Cre+ (no postnatal neurogenesis) to Cre- (wild type) littermate offspring. The results indicate that Cre+ mice are impaired relative to Cre- mice in the remote memory for a temporal based association task and in a novelty based spatial pattern separation task. These results support the temporal integration model of Aimone et al., [(2006) Nat Neurosci 9:723-727] and provide further support for an important role for postnatally born neurons in spatial pattern separation. In contrast, Cre+ mice are not impaired relative to Cre- mice in an object-context recognition task and a spatial location recognition task. These latter data suggest that postnatally derived neurons in the dentate gyrus (DG) do not support all spatial and object recognition functions of the DG.

The role of the ventral dentate gyrus in olfactory pattern separation.

Dorsoventral lesion studies of the hippocampus have indicated that the dorsal axis of the hippocampus is important for spatial processing and the ventral axis of the hippocampus is important for olfactory learning and memory and anxiety. There is some evidence to suggest that the ventral CA3 and ventral CA1 conduct parallel processes for pattern completion and temporal processing, respectively. Studies have indicated that the dorsal dentate gyrus (DG) is importantly involved in processes reflecting underlying pattern separation activity for spatial information. However, the ventral DG is less understood. The current study investigated the less-understood role of the ventral DG in olfactory pattern separation. A series of odor stimuli that varied on only one level, number of carbon chains (methyl groups), was used in a matching-to-sample paradigm in order to investigate ventral DG involvement in working memory for similar and less similar odors. Rats with ventral DG lesions were impaired at delays of 60 sec, but not at delays of 15 sec. A memory-based pattern separation effect was observed performance was poorest with only one carbon chain separation between trial odors and was highest for trials with four separations. The present study indicates that the ventral DG plays an important role in olfactory learning and memory processes for highly similar odors. The results also indicate a role for the ventral DG in pattern separation for odor information, which may have further implications for parallel processing across the dorsoventral axis for the DG in spatial (dorsal) and olfactory (ventral) pattern separation.

Erythropoietin improved cognitive function and decreased hippocampal caspase activity in rat pups after traumatic brain injury.

UNLABELLED: Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model. HYPOTHESIS: We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI). METHODS: EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2. RESULTS: EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury.

Dentate gyrus mediates cognitive function in the Ts65Dn/DnJ mouse model of Down syndrome.

In the Ts65Dn/DnJ mouse model of Down syndrome (DS), hippocampal deficits of learning and memory are the most robust features supporting this mouse as a valid cognitive model of DS. Although dentate gyrus (DG) dysfunction is suggested by excessive GABAergic inhibition, its role in perturbing DG functions in DS is unknown. We hypothesize that in the Ts65Dn/DnJ mouse, the specific role of the DG is disturbed in its support of contextual and spatial information. Support for this hypothesis comes from rats with DG lesions that show similar deficits. In order to test this hypothesis, we have developed a novel series of spontaneous exploratory tasks that emphasize the importance of recognizing spatial and contextual cues and that involve DG function. The results with this exploratory battery show that Ts65Dn/DnJ mice are impaired in DG-dependent short-term recognition tests involving object recognition with contextual cues, in place recognition and in metric distance recognition relative to wild type littermate controls. Further, whereas Ts65Dn/DnJ mice can recognize object novelty in the absence of contextual cues after a 5-min delay, they cannot do so after a delay of 24 h, suggesting a problem with CA1-mediated consolidation. The results also show that Ts65Dn/DnJ mice are not impaired in tasks (object recognition and configural object recognition) that are mediated by the perirhinal cortex (PRh). These results implicate the DG as a specific therapeutic target and the PRh as a potential therapeutic strength for future research to ameliorate learning and memory in DS.

Temporal associations for spatial events: the role of the dentate gyrus.

Previous research suggests that the dorsal dentate gyrus (DG) hippocampal subregion mediates spatial processing functions. However, a novel role for the DG in temporal processing for spatial information has begun to emerge based on the development of a computational model of neurogenesis. According to this model, adult born granule cells in the DG contribute to a temporal associative integration process for events presented closer in time. Currently, there is a paucity of behavioral evidence to support the temporal integration theory. Therefore, we developed a novel behavioral paradigm to investigate the role of the dDG in temporal integration for proximal and distal spatial events. Male Long-Evans rats were randomly assigned to a control group or to receive bilateral intracranial infusions of colchicine into the dDG. Following recovery from surgery, each rat was tested on a cued-recall of sequence paradigm. In this task, animals were allowed to explore identical objects placed in designated spatial locations on a cheeseboard maze across 2 days (e.g., Day 1: A and B; Day 2: C and D). One week later, animals were given a brief cue (A or C) followed by a preference test between spatial location B and D. Control animals had a significant preference for the spatial location previously paired with the cue (the temporal associate) whereas dDG lesioned animals failed to show a preference. These findings suggest that selective colchicine-induced dDG lesions are capable of disrupting the formation of temporal associations between spatial events presented close in time.

The role of the dorsal dentate gyrus in object and object-context recognition.

The aim of this study was to determine the role of the dorsal dentate gyrus (dDG) in object recognition memory using a black box and object-context recognition memory using a clear box with available cues that define a spatial context. Based on a 10 min retention interval between the study phase and the test phase, the results indicated that dDG lesioned rats are impaired when compared to controls in the object-context recognition test in the clear box. However, there were no reliable differences between the dDG lesioned rats and the control group for the object recognition test in the black box. Even though the dDG lesioned rats were more active in object exploration, the habituation gradients did not differ. These results suggest that the dentate gyrus lesioned rats are clearly impaired when there is an important contribution of context. Furthermore, based on a 24 h retention interval in the black box the dDG lesioned rats were impaired compared to controls.

A process analysis of the CA3 subregion of the hippocampus.

From a behavioral perspective, the CA3a,b subregion of the hippocampus plays an important role in the encoding of new spatial information within short-term memory with a duration of seconds and minutes. This can easily be observed in tasks that require rapid encoding, novelty detection, one-trial short-term or working memory, and one-trial cued recall primarily for spatial information. These are tasks that have been assumed to reflect the operations of episodic memory and require interactions between CA3a,b and the dentate gyrus (DG) via mossy fiber inputs into the CA3a,b. The CA3a,b is also important for encoding of spatial information requiring the acquisition of arbitrary and relational associations. All these tasks are assumed to operate within an autoassociative network function of the CA3 region. The CA3a,b also supports retrieval of short-term memory information based on a spatial pattern completion process. Based on afferent inputs into CA3a,b from the DG via mossy fibers and afferents from the entorhinal cortex into CA3a,b as well as reciprocal connections with the septum, CA3a,b can bias the process of encoding utilizing the operation of spatial pattern separation and the process of retrieval utilizing the operation of pattern completion. The CA3a,b also supports sequential processing of information in cooperation with CA1 based on the Schaffer collateral output from CA3a,b to CA1. The CA3c function is in part based on modulation of the DG in supporting pattern separation processes.