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.

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.

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.

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.

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.

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 medial and lateral entorhinal cortex both contribute to contextual and item recognition memory: a test of the binding of items and context model.

It has been suggested that the role of the hippocampus for episodic memory is to selectively bind together item and contextual information. One such model, the Binding of Items and Context (BIC) model, proposed that the perirhinal cortex provides item and the postrhinal/parahippocampal cortex provides context to the hippocampus via the medial (MEC) and lateral entorhinal cortices (LEC) to be bound into an episodic representation. This model proposes that item and context information are stored and processed independently and in parallel before hippocampal processing. To evaluate this model, the present experiment evaluated the role of the MEC and LEC for item and contextual novelty detection. The present results suggest that excitotoxic lesions to the LEC primarily disrupt item novelty detection, whereas lesions to the MEC primarily disrupt contextual novelty detection. These data provide a functional double dissociation between the MEC and LEC across item and contextual processing. Despite this dissociation, the present results suggest that item and contextual information are not represented independently before hippocampal processing. These data support the basic assumptions of the BIC model, but suggest that item and context information may interact in the entorhinal cortex.

The role of the dentate gyrus in the formation of contextual representations.

The hippocampus is involved in encoding and integrating contextual information. Recently, it has been suggested that the dorsal dentate gyrus (dDG) hippocampal subregion may mediate the formation of contextual representations of the spatial environment through a conjunctive encoding process whereby incoming multimodal information is integrated into a single higher-order representation. Despite anatomical evidence in support of this claim, behavioral evidence is limited. Therefore, a contextual associative learning paradigm was used to determine whether the dDG supports the formation of integrated contextual representations. Male Long-Evans rats were randomly assigned as controls or to receive bilateral intracranial infusions of colchicine into the dDG. Following recovery from surgery, each rat was tested on an appetitive task that required animals to form an association between a cue (odor) and a context to receive a food reward. Each rat received 10 trials per day and was tested for 10 consecutive days. Upon completion of testing, animals were tested on an additional two-choice olfactory and contextual discrimination task. The testing order was counterbalanced across animals. Results showed that control animals successfully acquired the contextual associative learning task for olfactory stimuli as indicated by improved performance across the 10 testing days. In contrast, animals with dDG lesions were impaired in the ability to acquire the odor-context associations. Results from follow-up odor and context discrimination tests indicated that both groups acquired the discriminations at similar rates. Therefore, it is unlikely that deficits in performance on the contextual associative learning task were due to an inability to discriminate between odors or contexts. The present findings provide further support for DG involvement in the formation of conjunctive contextual representations.

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.

Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations.

The hippocampus (HPP) plays a known role in learning novel spatial information. More specifically, the dentate gyrus (DG) hippocampal subregion is thought to support pattern separation, a mechanism for encoding and separating spatially similar events into distinct representations. Several studies have shown that lesions of the dorsal DG (dDG) in rodents result in inefficient spatial pattern separation for working memory; however, it is unclear whether selective dDG lesions disrupt spatial pattern separation for reference memory. Therefore, the current study investigated the role of the dDG in pattern separation using a spatial reference memory paradigm to determine whether the dDG is necessary for acquiring spatial discriminations for adjacent locations. Male Long-Evans rats were randomly assigned to receive bilateral intracranial infusions of colchicine or saline (control) into the dDG. Following recovery from surgery, each rat was pseudo-randomly assigned to an adjacent arm or separate arm condition and subsequently tested on a place-learning task using an eight-arm radial maze. Rats were trained to discriminate between a rewarded arm and a nonrewarded arm that were either adjacent to one another or separated by a distance of two arm positions. Each rat received 10 trials per day and was tested until the animal reached a criterion of nine correct choices out of 10 consecutive trials across 2 consecutive days of testing. Both groups acquired spatial discriminations for the separate condition at similar rates. However, in the adjacent condition, dDG lesioned animals required significantly more trials to reach the learning criterion than controls. The results suggest that dDG lesions decrease efficiency in pattern separation resulting in impairments in the adjacent condition involving greater overlap among the distal cues. Conversely, in the separate condition, there was less overlap among distal cues during encoding and less need for pattern separation. These findings provide further support for a critical role for the dDG in spatial pattern separation by demonstrating the importance of a processing mechanism that is capable of reducing interference among overlapping spatial inputs across a variety of memory demands.

The role of the dorsal and ventral hippocampus in olfactory working memory.

Olfactory working memory and pattern separation for odor information was assessed in male rats using a matching-to-sample for odors paradigm. The odor set consisted of a five aliphatic acids with unbranched carbon chains that varied from two- to six-carbons in length. Each trial consisted of a sample phase followed by a choice phase. During the sample phase, rats would receive one of five different odors. Fifteen seconds later during the choice phase one of the previous odors was presented simultaneously side by side with a different odor that was based on the number of aliphatic acids that varied in the carbon chains from two- to six-carbons in length and rats were allowed to choose between the two odors. The rule to be learned in order to receive a food reward was to always choose the odor that occurred during the study phase. Odor separations of 1, 2, 3 or 4 were selected for each choice phase and represented the carbon chain difference between the study phase odor and the test phase odor. Once an animal reached a criterion of 80-90% correct across all temporal separations based on 40 trials, rats received a control, dorsal hippocampal, or ventral hippocampal lesion and were retested on the task. On postoperative trials, only the ventral hippocampal lesion group was impaired relative to both control and dorsal hippocampal groups groups. There were no effects on odor pattern separation. All groups of rats could discriminate between the odors. The data suggest that the ventral hippocampus, but not dorsal hippocampus, supports working memory for odor information.

An analysis of rat prefrontal cortex in mediating executive function.

While it is acknowledged that species specific differences are an implicit condition of comparative studies, rodent models of prefrontal function serve a significant role in the acquisition of converging evidence on prefrontal function across levels of analysis and research techniques. The purpose of the present review is to examine whether the prefrontal cortex (PFC) in rats supports a variety of processes associated with executive function including working memory, temporal processing, planning (prospective coding), flexibility, rule learning, and decision making. Therefore, in this review we examined changes associated with working memory processes for spatial locations, visual objects, odors, tastes, and response domains or attributes, temporal processes including temporal order, sequence learning, prospective coding, behavioral flexibility associated with reversal learning and set shifting, paired associate learning, and decision making based on effort, time discounting, and uncertainty following damage to the PFC in rats. In addition, potential parallel processes of executive function in monkeys and humans based on several theories of subregional differentiation within the PFC will be presented. Specifically, theories based on domain or attribute specificity (Goldman-Rakic, 1996), level of processing (Petrides, 1996), rule learning based on complexity (Wise, Murray, & Gerfen, 1996), executive functions based on connectivity with other brain regions associated with top-down control (Miller & Cohen, 2001), are presented and applied to PFC function in rats with the aim of understanding subregional specificity in the rat PFC. The data suggest that there is subregional specificity within the PFC of rats, monkey and humans and there are parallel cognitive functions of the different subregions of the PFC in rats, monkeys and humans.

Implications of CA3 NMDA and opiate receptors for spatial pattern completion in rats.

Theoretical models of the CA3 suggest that because of its architecture, it mediates spatial pattern completion and working memory processes. The aim of this study was to determine whether with the use of drugs to block neurotransmitter action in CA3 one can separate the operation of these two processes using a visual-spatial pattern completion task for multiple cues. Rats were trained on a cheeseboard apparatus with a black curtain containing four extramaze cues. In the study phase rats removed a black block from one of 15 food wells and then after a 10- or 30-s delay in the test phase they had to return to the food well in the absence of the black block. After reaching criterion performance cannulae were bilaterally implanted into the CA3 of the rats. Rats were then given AP5, naloxone, or phosphate buffered saline (PBS) and following the standard study phase they were given the test phase with 0, 1, 2, 3, or 4 cues removed. The mean degree of error in all drugs and all cue conditions was recorded. Overall spatial inaccuracy was recorded in rats under the AP5 30-s delay condition, whereas deficits were contingent upon the number of cues available under all naloxone conditions. Results show that the blockage of glutamate via AP5 inhibited short-term or working memory, whereas the blockage of mu-opioids via naloxone disrupted visual-spatial pattern completion.

The role of the dorsal CA1 and ventral CA1 in memory for the temporal order of a sequence of odors.

Memory for the temporal order of a sequence of odors was assessed in male rats. A sequence of five odors mixed in sand was presented in digging cups one at a time to each rat in a sequence that varied on each trial. A reward was buried in each cup. Following the fifth odor, two of the previous five odors were presented simultaneously and the rat needed to choose the odor that occurred earliest in the sequence to receive a reward. Temporal separations of 1, 2, or 3 were used which represented the number of odors that occurred between the two odors in the sequence. Once pre-operative criterion was reached, rats received a control, dorsal CA1 (dCA1), or ventral CA1 (vCA1) lesion and were retested on the task. On post-operative trials, only the vCA1 group was impaired relative to both control and dCA1 groups. All groups of rats could discriminate between the odors. The data suggest that the vCA1, but not dorsal CA1, is involved in separating sensory events (odors) in time so that one odor can be remembered separate from another odor.

Prefrontal and hippocampal contributions to encoding and retrieval of spatial memory.

The prefrontal cortex is thought to be critical for goal-directed action and the hippocampus is known to be importantly involved in spatial memory. Several studies have been suggestive of a role for the orbitofrontal cortex (OFC) in spatial navigation. However, the medial prefrontal cortex (mPFC) receives projections directly from the intermediate CA1 (iCA1) region of hippocampus and this link may be critical for spatial navigation. The purpose of the present investigation was to test the performance of rats receiving bilateral or disconnection infusions of lidocaine into OFC, mPFC, or iCA1 to determine the contribution of these structures to encoding and retrieval of spatial memory using the Hebb-Williams maze. A total of 92 male Long-Evans rats received chronic bilateral, contralateral, or ipsilateral implantation of cannulas into OFC, mPFC, or iCA1. Prior to testing on day 1 or day 2, subjects received central infusions of saline or lidocaine. The number of errors committed on the first five trials compared to the second five trials of day 1 was used to determine encoding, whereas retrieval was determined by comparing the second five trials of day 1 with the first five trials of day 2. The present findings suggest that mPFC and iCA1 are necessary and interact during encoding and retrieval; however, the OFC does not appear to be essential for either process. While the nature of the interaction between mPFC and iCA1 during encoding and retrieval is unclear, it may be supported by the integration of goals and spatial cues or strategy switching.

The posterior parietal cortex and long-term memory representation of spatial information.

The hypothesis to be explored in this chapter is based on the assumption that the posterior parietal cortex (PPC) is directly involved in representing a subset of the spatial features associated with spatial information processing and plays an important role in perceptual memory as well as long-term memory encoding, consolidation, and retrieval of spatial information. After presentation of the anatomical location of the PPC in rats, the nature of PPC representation based on single spatial features, binding of visual features associated with visual spatial attention, binding of object-place associations associated with acquisition and storage of associations where one of the elements is a spatial component, and binding of ideothetic and allothetic information in long-term memory is discussed. Additional evidence for a PPC role in mediation of spatial information in long-term storage is offered. Finally, the relationship between the PPC and the hippocampus from a systems and dynamic point view is presented.