Sequential order spatial memory in male rats: Characteristics and impact of medial prefrontal cortex and hippocampus disruption.

Remembering an experience entails linking what happened, where the event transpired, and when it occurred. Most rodent hippocampal studies involve tests of spatial memory, but fewer investigate temporal and sequential order memory. Here we provide a demonstration of rats learning an aversive sequential order task using a radial arm water maze. Male rats learned a fixed sequence of up to seven spatial locations, with each decision session separated by a temporal delay. Rats relied on visuospatial cues and the number of times they had entered the maze for a given day in order to successfully perform the task. Behavioral patterns during asymptotic performance showed similarities to the serial-position effect, especially with regards to faster first choice latency. Rats at asymptotic performance were implanted with bilateral cannula in medial prefrontal cortex, dorsal, and ventral hippocampus. After re-training, we injected muscimol to temporarily disrupt targeted brain regions. While control rats made prospective errors, rats with mPFC muscimol exhibited more retrospective errors. Rats with hippocampal muscimol no longer exhibited a prospective bias and were at chance levels in their error choices. Taken together, our results suggest disruption of mPFC, but not the hippocampus, produced an error choice bias during an aversive sequential order spatial processing task.

Social factors influence solo and rat dyads exploration of an unfamiliar open field.

Exploring new and unfamiliar environments is critical for survival, providing information on food, shelter, mates, and sources of danger. The open field paradigm is commonly used to study exploration and anxiety-like behaviors in the lab. Many social animals, like humans and rats, may explore their environments in social groups; however, relatively few studies have investigated the influence of conspecifics on open field activity. Here, we provide a comparison of individual (solo) or pairs of male rats (dyads) exploring and interacting across repeated exposures to an unfamiliar (Day 1) or more familiar (Day 2) open field. Both solo rats and dyads explored a larger area, traveled further, and spent less time near the maze walls on the second maze exposure. Solo rats explored a larger area and spent less time near the maze walls than dyads on both days because dyads spent more time socializing rather than exploring the environment. Furthermore, we compared familiar dyads that were co-housed for seven days versus stranger dyads that met for the first time in the open field. While familiar and stranger dyads did not differ in maze exploration, strangers spent more time interacting nose to nose than nose to anogenital. These results indicate that the degree of familiarity with the environment does not interact with the tendency of dyads to socialize rather than explore the environment.

Age-related decrease in theta and gamma coherence across dorsal ca1 pyramidale and radiatum layers.

In both humans and rodents, aging is linked to impairments in hippocampus dependent learning. Given such deficits, one would expect corresponding changes in hippocampal local field potentials, which represent the integration of multiple inputs onto a given dendritic field within the hippocampus. The current experiment examined coherence of theta and gamma in young and aged rats at sub-millimeter and millimeter distant locations both within and across layers in CA1 of the dorsal hippocampus. The degree to which different dendritic layers show coherent oscillations indicates the uniformity of the inputs and local circuitry, and may form an important element for processing information. Aged rats had lower coherence in all frequency ranges; this was most marked within a layer as the distance between electrodes increased. Notably, unlike younger rats, in the aged rats coherence was not affected by running on the maze. Furthermore, despite the previously reported effects of cholinergic activation on theta frequency and power, there was no effect of the cholinomimetic physostigmine on coherence. These data indicate an age related fragmentation in hippocampal processing that may underlie some of the observed learning and memory deficits.

Dissociation between dorsal and ventral hippocampal theta oscillations during decision-making.

Hippocampal theta oscillations are postulated to support mnemonic processes in humans and rodents. Theta oscillations facilitate encoding and spatial navigation, but to date, it has been difficult to dissociate the effects of volitional movement from the cognitive demands of a task. Therefore, we examined whether volitional movement or cognitive demands exerted a greater modulating factor over theta oscillations during decision-making. Given the anatomical, electrophysiological, and functional dissociations along the dorsal-ventral axis, theta oscillations were simultaneously recorded in the dorsal and ventral hippocampus in rats trained to switch between place and motor-response strategies. Stark differences in theta characteristics were found between the dorsal and ventral hippocampus in frequency, power, and coherence. Theta power increased in the dorsal, but decreased in the ventral hippocampus, during the decision-making epoch. Interestingly, the relationship between running speed and theta power was uncoupled during the decision-making epoch, a phenomenon limited to the dorsal hippocampus. Theta frequency increased in both the dorsal and ventral hippocampus during the decision epoch, although this effect was greater in the dorsal hippocampus. Despite these differences, ventral hippocampal theta was responsive to the navigation task; theta frequency, power, and coherence were all affected by cognitive demands. Theta coherence increased within the dorsal hippocampus during the decision-making epoch on all three tasks. However, coherence selectively increased throughout the hippocampus (dorsal to ventral) on the task with new hippocampal learning. Interestingly, most results were consistent across tasks, regardless of hippocampal-dependent learning. These data indicate increased integration and cooperation throughout the hippocampus during information processing.

Conflict between place and response navigation strategies: effects on vicarious trial and error (VTE) behaviors.

Navigation can be accomplished through multiple decision-making strategies, using different information-processing computations. A well-studied dichotomy in these decision-making strategies compares hippocampal-dependent "place" and dorsal-lateral striatal-dependent "response" strategies. A place strategy depends on the ability to flexibly respond to environmental cues, while a response strategy depends on the ability to quickly recognize and react to situations with well-learned action-outcome relationships. When rats reach decision points, they sometimes pause and orient toward the potential routes of travel, a process termed vicarious trial and error (VTE). VTE co-occurs with neurophysiological information processing, including sweeps of representation ahead of the animal in the hippocampus and transient representations of reward in the ventral striatum and orbitofrontal cortex. To examine the relationship between VTE and the place/response strategy dichotomy, we analyzed data in which rats were cued to switch between place and response strategies on a plus maze. The configuration of the maze allowed for place and response strategies to work competitively or cooperatively. Animals showed increased VTE on trials entailing competition between navigational systems, linking VTE with deliberative decision-making. Even in a well-learned task, VTE was preferentially exhibited when a spatial selection was required, further linking VTE behavior with decision-making associated with hippocampal processing.

Hippocampal theta, gamma, and theta-gamma coupling: effects of aging, environmental change, and cholinergic activation.

Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics of encoding and retrieval. One major influence on hippocampal rhythmicity is from cholinergic afferents. In both humans and rodents, aging is linked to impairments in hippocampus-dependent function along with degradation of cholinergic function. Cholinomimetics can reverse some age-related memory impairments and modulate oscillations in the hippocampus. Therefore, one would expect corresponding changes in these oscillations and possible rescue with the cholinomimetic physostigmine. Hippocampal activity was recorded while animals explored a familiar or a novel maze configuration. Reexposure to a familiar situation resulted in minimal aging effects or changes in theta or gamma oscillations. In contrast, exploration of a novel maze configuration increased theta power; this was greater in adult than old animals, although the deficit was reversed with physostigmine. In contrast to the theta results, the effects of novelty, age, and/or physostigmine on gamma were relatively weak. Unrelated to the behavioral situation were an age-related decrease in the degree of theta-gamma coupling and the fact that physostigmine lowered the frequency of theta in both adult and old animals. The results indicate that age-related changes in gamma and theta modulation of gamma, while reflecting aging changes in hippocampal circuitry, seem less related to aging changes in information processing. In contrast, the data support a role for theta and the cholinergic system in encoding and that hippocampal aging is related to impaired encoding of new information.

Changes in task demands alter the pattern of zif268 expression in the dentate gyrus.

Granule cells of the dentate gyrus (DG) are thought to disambiguate similar experiences--a process termed pattern separation. Using zif268 as a marker of cellular activity, DG function was assessed in rats performing two tasks: a place task (go east) and a response task (turn right). As these tasks occurred within the same physical space (a plus maze) without any physical cue to indicate the correct strategy in a given trial, this scenario critically involves disambiguation of task demands and presumably pattern separation. Performance of the two tasks induced zif268 expression in distinct populations of granule cells within the suprapyramidal but not the infrapyramidal blade of the DG. Repeated performance of the same task (i.e., two response-task trials or two place-task trials), however, elicited zif268 expression within a single subset of the granule cell population. This differential transcription pattern shows that the retrieval of different behavioral strategies or mnemonic demands recruit distinct ensembles of granule cells, possibly to prevent interference between memories of events occurring within the same physical space to permit the selection of appropriate responses.

Cognitive demands induce selective hippocampal reorganization: Arc expression in a place and response task.

Place cells in the hippocampus can maintain multiple representations of a single environment and respond to physical and/or trajectory changes by remapping. Within the hippocampus there are anatomical, electrophysiological, and behavioral dissociations between the dorsal and ventral hippocampus and within dorsal CA1. Arc expression was used to measure the recruitment of ensembles across different hippocampal subregions in rats trained to utilize two different cognitive strategies while traversing an identical trajectory. This behavioral paradigm allowed for the measurement of remapping in the absence of changes in external cues, trajectory traversed (future/past), running speed, motivation, or different stages of learning. Changes in task demands induced remapping in only some hippocampal regions: reorganization of cell ensembles was observed in dorsal CA1 but not in dorsal CA3. Moreover, a gradient was found in the degree of remapping within dorsal CA1 that corresponds to entorhinal connectivity to this region. Remapping was not seen in the ventral hippocampus: neither ventral CA1 nor CA3 exhibited ensemble changes with different cognitive demands. This contrasts with findings of remapping in both the dorsal and ventral dentate gyrus using this task. The results suggest that the dorsal pole of the hippocampus is more sensitive to changes in task demands.

Theta and gamma coherence across the septotemporal axis during distinct behavioral states.

Theta (4-12 Hz) and gamma (40-100 Hz) field potentials represent the interaction of synchronized synaptic input onto distinct neuronal populations within the hippocampal formation. Theta is quite prominent during exploratory activity, locomotion, and REM sleep. Although it is generally acknowledged that theta is coherent throughout most of the hippocampus, there is significant variability in theta, as well as gamma, coherence across lamina at any particular septotemporal level of the hippocampus. Larger differences in theta coherence are observed across the septotemporal (long) axis. We have reported that during REM sleep there is a decrease in theta coherence across the long axis that varies with the topography of CA3/mossy cell input rather than the topography of the prominent entorhinal input. On the basis of differences in the rat's behavior as well as the activity of neuromodulatory inputs (e.g., noradrenergic and serotonergic), we hypothesized that theta coherence across the long axis would be greater during locomotion than REM sleep and exhibit a pattern more consistent with the topography of entorhinal inputs. We examined theta and gamma coherence indices at different septotemporal and laminar sites during distinct theta states: locomotion during maze running, REM sleep, following acute treatment with a θ-inducing cholinomimetic (physostigmine) and for comparison during slow-wave sleep. The results demonstrate a generally consistent pattern of theta and gamma coherence across the septotemporal axis of the hippocampus that is quite indifferent to sensory input and overt behavior. These results are discussed with regards to the neurobiological mechanisms that generate theta and gamma and the growing body of evidence linking theta and gamma indices to memory and other cognitive functions.

Observational learning of a shifting goal location in rats: Impact of distance, observed performance, familiarity, and delay.

BACKGROUND: Observational learning allows for learning without direct exposure to danger or energetic demands. This form of learning is seen in humans, other primates, and other species such as rodents. The neurobiology behind social learning has been studied mostly in rats, specifically focusing on social transmission of food preference and fear. However, less is known regarding the neural circuitry behind social learning of a foraging scenario. NEW METHOD: The current study examined observational learning in a working memory Tmaze task. The food location changed daily such that the observing animal had to learn the correct location anew each day. This delineated the time frame when an animal learned by observation, making the phenomenon easier to study. RESULTS: Rats learned the location of a food reward by observing a conspecific. Furthermore, the distance of the rats from the maze affected performance. Additionally, performance was affected by whether the performer made mistakes. This memory could persist for at least five minutes. Lastly, performance was not affected by observer-demonstrator familiarity COMPARISON WITH EXISTING METHODS: Previous rodent foraging studies typically exposed observers to the same behavior over many observation sessions. In this scenario, it is difficult to determine when and how an animal learns through observation. The current task delineates the period of observation in each session, allowing manipulations during the observation period. CONCLUSIONS: The current paradigm allows for repeated examinations of observational learning and provides an alternative method for neurobiological studies of social learning.

Activation of the medial septum reverses age-related hippocampal encoding deficits: a place field analysis.

When a rat runs through a familiar environment, the hippocampus retrieves a previously stored spatial representation of the environment. When the environment is modified a new representation is seen, presumably corresponding to the hippocampus encoding the new information. The medial septum is hypothesized to modulate whether the hippocampus engages in retrieval or encoding. The cholinergic agonist carbachol was infused into the medial septum, and hippocampal CA1 place cells were recorded in freely moving rats. In a familiar environment, septal activation impaired the retrieval of a previously stored hippocampal place cell representation regardless of age. When the environment was changed, medial septal activation impaired the encoding process in young, but facilitated the encoding of the new information in aged rats. Moreover, the improved encoding was evident during a subsequent exposure to the modified environment 24 h later. The findings support the role the septum plays in modulating hippocampal retrieval/encoding states. Furthermore, our data indicate a mechanism of age-related cognitive impairment.

Scopolamine induced deficits in a battery of rat cognitive tests: comparisons of sensitivity and specificity.

Despite much research, the cognitive effects of scopolamine hydrobromide, a cholinergic antagonist, remain controversial. Scopolamine affects multiple systems each of which can impact behavior. One way to tease apart the effects of the drug is to determine the effects of low scopolamine doses on different abilities. The present experiments compared the effects of low doses of scopolamine on a single group of rats conducting a battery of behavioral tasks: Morris water maze, radial arm maze, delayed non-matching to position tasks, and fixed ratio 5 bar pressing. The behavioral battery ranged from tasks having little cognitive demand to those thought to be based more on attention and spatial-working memory. Control experiments using additional groups of rats assessing peripheral versus central effects were conducted with both liquid and dry reinforcement and with methyl scopolamine. Furthermore, the 5-choice serial reaction time test assessed scopolamine effects on attention. The data show a wide spectrum of central and peripheral cholinergic involvement. The central effects include attention and motor initiation, both of which impact and interact with the mnemonic function of acetylcholine. These results show that a limited disruption of the central cholinergic system can have profound effects on attention and/or psychomotor control before any measurable mnemonic disruption.

Interdependence between dorsal and ventral hippocampus during spatial navigation.

INTRODUCTION: The hippocampus is linked to the formation and retrieval of episodic memories and spatial navigation. In rats, it is an elongated structure divided into dorsal (septal) and ventral (temporal) regions paralleling the respective division in the posterior and anterior hippocampus in humans. The dorsal hippocampus has been suggested to be more important for spatial processing and the ventral to processing anxiety-based behaviors. Far less is known regarding the degree to which these different regions interact during information processing. The anatomical connectivity suggests a flow of information between the dorsal and ventral regions; conversely, there are also commissural connections to the contralateral hippocampus. The current study examined the extent to which information from the dorsal hippocampus interacts with processing in the ipsilateral and contralateral ventral hippocampus following the acquisition of a spatial task. METHODS: Rats were well-trained on a spatial reference version of the water maze, followed by muscimol inactivation of different hippocampal subregions in a within-animal repeated design. Various combinations of bilateral, ipsilateral, and contralateral infusions were used. RESULTS: Combined dorsal and ventral inactivation produced a severe impairment in spatial performance. Inactivation of only the dorsal or ventral regions resulted in intermediate impairment with performance levels falling between controls and combined inactivation. Performance was impaired during contralateral inactivation and was almost equivalent to bilateral dorsal and ventral hippocampus inactivation, while ipsilateral inactivation resulted in little impairment. CONCLUSIONS: Taken together, results indicate that for spatial processing, the hippocampus functions as a single integrated structure along the longitudinal axis.

Does the dorsal hippocampus process navigational routes or behavioral context? A single-unit analysis.

In humans the hippocampus plays a role in both episodic memory and spatial navigation. Similar findings have been shown in other animals including monkeys and rats. The relationship between the processing of episodic and spatial related inputs within the hippocampus remains a puzzle. One approach to understanding how the hippocampus processes information is to examine how hippocampal cell activity corresponds to environmental experience. Hippocampal pyramidal cells can alter their spatial tuning (re-map) in response to changes in task demands. The degree to which this re-mapping is related to contextual/episodic information or to changes in spatial navigation/trajectories is unclear. The current study was designed to examine cell activity under two conditions that differed in contextual information without alterations in the goal-directed trajectories taken by the animals. Adult and aged rats were trained to do an alternation task on a fixed pathway [J. A. Oler et al. (2005)Neuroscience, 131, 1-12]. The animals ran this pathway during either 'safe' or 'unsafe' (a tone indicating a shock region) trials, with hesitation during 'unsafe' trials providing a clear behavioral measure of discrimination between these two conditions. Relatively few place cells displayed re-mapping between the two conditions. We propose that the principle source of re-mapping in the dorsal hippocampus is changes in the animal's trajectories rather than behavioral context. Possible reasons why so few cells responded to the change in context are discussed.

Human sex differences in solving a virtual navigation problem.

The current study examined sex differences in initial and subsequent strategies in solving a navigational problem within a virtual reality environment. We tested 163 undergraduates on a virtual T-maze task that included probe trials designed to assess whether participants were responding using either a place or response strategy. Participants were also tested on a mental rotation task and memory of the details of the virtual room. There were no differences between the sexes in copying or recalling a map of the room or on first trial performance of the T-maze. However, at trial two, males show a significant advantage in solving the task, and approximately 80% of the males adopt a place strategy to solve the T-maze whereas females at that point showed no strategy preference. Across all testing, both males and females preferentially used a place strategy. We discuss how factors such as spatial priming affect strategy preferences and how such factors may differentially affect males and females.

Sex differences and correlations in a virtual Morris water task, a virtual radial arm maze, and mental rotation.

Different tasks are often used to assess spatial memory in humans compared to nonhumans. In order to bridge this paradigmatic gap, we used a within-subject design to test 61 undergraduates on three spatial memory tasks. One of these tasks, the Vanderberg 3D mental rotation task, is classically used to assess spatial memory in humans. The other two tests are virtual analogues of two tasks used classically to assess spatial memory in rodents: the Morris water task and an eight-arm radial maze. We find that males perform significantly better than females on the mental rotation task and in finding a hidden platform in the virtual Morris water task. Moreover, during a probe trial, males spend significantly more distance of their swim in the training quadrant, but males and females do not differ in navigating to a visible platform. However, for the virtual eight-arm radial maze, there is no sex difference in working memory errors, reference memory errors, or distance to find the rewards. Surprisingly, an examination of the correlations among the three tasks indicates that only mental rotation ability and Morris water task probe trial performance correlate significantly among the three tasks (i.e. there are no significant correlations with traditional measures the tasks, e.g. time or distance to completion). Hence, the Morris water task and the eight-arm radial maze do not assess spatial memory in the same manner, and even after equating factors such as motivation, stress, and motor demands, there still are procedural demands of the tasks that reinforce differential strategy selection during spatial memory. This suggests that caution should be taken when utilizing these two tasks interchangeable as tests of spatial memory.

Novel space alters theta and gamma synchrony across the longitudinal axis of the hippocampus.

Hippocampal theta (6-10 Hz) and gamma (25-50 Hz and 65-100 Hz) local field potentials (LFPs) reflect the dynamic synchronization evoked by inputs impinging upon hippocampal neurons. Novel experience is known to engage hippocampal physiology and promote successful encoding. Does novelty synchronize or desynchronize theta and/or gamma frequency inputs across the septotemporal (long) axis of the hippocampus (HPC)? The present study tested the hypothesis that a novel spatial environment would alter theta power and coherence across the long axis. We compared theta and gamma LFP signals at individual (power) and millimeter distant electrode pairs (coherence) within the dentate gyrus (DG) and CA1 region while rats navigated a runway (1) in a familiar environment, (2) with a modified path in the same environment and (3) in a novel space. Locomotion in novel space was related to increases in theta and gamma power at most CA1 and DG sites. The increase in theta and gamma power was concurrent with an increase in theta and gamma coherence across the long axis of CA1; however, there was a significant decrease in theta coherence across the long axis of the DG. These findings illustrate significant shifts in the synchrony of entorhinal, CA3 and/or neuromodulatory afferents conveying novel spatial information to the dendritic fields of CA1 and DG targets across the long axis of the HPC. This shift suggests that the entire theta/gamma-related input to the CA1 network, and likely output, receives and conveys a more coherent message in response to novel sensory experience. Such may contribute to the successful encoding of novel sensory experience.

Extensive training and hippocampus or striatum lesions: effect on place and response strategies.

The hippocampus has been linked to spatial navigation and the striatum to response learning. The current study focuses on how these brain regions continue to interact when an animal is very familiar with the task and the environment and must continuously switch between navigation strategies. Rats were trained to solve a plus maze using a place or a response strategy on different trials within a testing session. A room cue (illumination) was used to indicate which strategy should be used on a given trial. After extensive training, animals underwent dorsal hippocampus, dorsal lateral striatum or sham lesions. As expected hippocampal lesions predominantly caused impairment on place but not response trials. Striatal lesions increased errors on both place and response trials. Competition between systems was assessed by determining error type. Pre-lesion and sham animals primarily made errors to arms associated with the wrong (alternative) strategy, this was not found after lesions. The data suggest a qualitative change in the relationship between hippocampal and striatal systems as a task is well learned. During acquisition the two systems work in parallel, competing with each other. After task acquisition, the two systems become more integrated and interdependent. The fact that with extensive training (as something becomes a "habit"), behaviors become dependent upon the dorsal lateral striatum has been previously shown. The current findings indicate that dorsal lateral striatum involvement occurs even when the behavior is spatial and continues to require hippocampal processing.

Disambiguating the similar: the dentate gyrus and pattern separation.

The human hippocampus supports the formation of episodic memory without confusing new memories with old ones. To accomplish this, the brain must disambiguate memories (i.e., accentuate the differences between experiences). There is convergent evidence linking pattern separation to the dentate gyrus. Damage to the dentate gyrus reduces an organism's ability to differentiate between similar objects. The dentate gyrus has tenfold more principle cells than its cortical input, allowing for a divergence in information flow. Dentate gyrus granule neurons also show a very different pattern of representing the environment than "classic" place cells in CA1 and CA3, or grid cells in the entorhinal cortex. More recently immediate early genes have been used to "timestamp" activity of individual cells throughout the dentate gyrus. These data indicate that the dentate gyrus robustly differentiates similar situations. The degree of differentiation is non-linear, with even small changes in input inducing a near maximal response in the dentate. Furthermore this differentiation occurs throughout the dentate gyrus longitudinal (dorsal-ventral) axis. Conversely, the data point to a divergence in information processing between the dentate gyrus suprapyramidal and infrapyramidal blades possibly related to differences in organization within these regions. The accumulated evidence from different approaches converges to support a role for the dentate gyrus in pattern separation. There are however inconsistencies that may require incorporation of neurogenesis and hippocampal microcircuits into the currents models. They also suggest different roles for the dentate gyrus suprapyramidal and infrapyramidal blades, and the responsiveness of CA3 to dentate input.

Age-related decline in auditory plasticity: experience dependent changes in gap detection as measured by prepulse inhibition in young and aged rats.

Young adult and aged F344 rats were compared on a silent gap variant of the prepulse inhibition paradigm. Animals were tested using a 50-ms single tone cue, followed by 8 days of silent gap testing. The first 3 days of gap testing were long gaps (range 2 to 100 ms) followed by 5 days of short gaps (range 2 to 10 ms). The effects of gap length, prior experience, and age, on the magnitude and direction (facilitation vs. attenuation) of the acoustic startle response, were examined. The young rats showed stronger and more reliable acoustic startle responses (uncued trials) during all acoustic startle tasks as compared to the old. The younger animals also exhibited a more consistent attenuated response across cues and days. Depending on silent gap length, both reduction (inhibition) and enhancement (facilitation) of startle were observed. Finally, only the young adult animals showed an experience-related shift from facilitation to attenuation in response to very short silent gap cues, and this initial early facilitation predicted later attenuation following additional experience.