Phosphorylation state of CREB in the rat hippocampus: a molecular switch between spatial novelty and spatial familiarity?

The activation of cAMP response element-binding protein (CREB) after a learning experience is a common feature in the formation of several associative memories. We recently demonstrated that the increase in the hippocampal phosphorylated CREB (pCREB) levels 1 h after a short exploration of an open field (OF) was associated to detection of spatial novelty and was not related to the memory formation of habituation in this non-associative learning paradigm. Moreover, after a long training of three OF sessions, hippocampal pCREB levels were below to that observed in control rats. The present results show that such decrease does not correlate with memory retrieval or improvement in long-term memory of habituation. Instead, it is associated with the familiarity to the arena. Our experiments revealed that the relevant variable to induce CREB deactivation was the prolonged exploration of the arena (30 min). A 15 min OF exploration was ineffective. Furthermore, the last 5 min period of a prolonged exploration was crucial to change CREB phosphorylation state: when exploration took place in a novel arena the level of pCREB increased; in contrast, when it was performed in the familiar OF, pCREB levels decreased. Taken as a whole, our results suggest that CREB phosphorylation state in the hippocampus switches in response to exposure to a novel or to a familiar spatial environment.     

Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts

Rats have a natural tendency to spend more time exploring novel objects than familiar objects, and this preference can be used as an index of object recognition. Rats also show an exploratory preference for objects in locations where they have not previously encountered objects (an index of place memory) and for familiar objects in contexts different from those in which the objects were originally encountered (an index of context memory). In this experiment, rats with cytotoxic lesions of the hippocampal formation were tested on all three versions of the novelty-preference paradigm, with a 5-min retention interval between the familiarization and test phases. Rats with sham lesions displayed a novelty preference on all three trial types, whereas the rats with hippocampal lesions displayed a novelty preference on Object trials but did not discriminate between the objects on Place trials or Context trials. The findings indicate that hippocampal damage impairs memory for contextual or spatial aspects of an experience, whereas memory for objects that were part of the same experience are left relatively intact.     

Hippocampal formation lesions impair performance in an odor-odor association task independently of spatial context

The rodent hippocampal system is known to play an important role in memory. Evidence that this role is not limited to spatial memory has come from studies using a variety of non-spatial memory tasks. One example is the social transmission of food preference paradigm, a task in which rats learn an odor-odor association with no explicit spatial memory component. However, because training and testing in this task typically take place in the same environment, it is possible that memory for the spatial context in which odors are experienced during training is critical to subsequent retention performance. If this is the case, it might be expected that lesions of the hippocampal system would impair memory performance by disrupting the establishment of a representation of the training environment. We addressed this issue by training rats in one spatial context and then testing them either in the same or a different spatial context. Normal control rats performed equally well when tested in an environment that was the same or different from that used during training, and the retention impairment exhibited by rats with hippocampus plus subiculum lesions was equivalent in the two test environments. These results support the view that the hippocampal system is necessary for the flexible expression of nonspatial memories even when the spatial context in which the memory is acquired is not critical to retrieval.     

Memory influences on hippocampal and striatal neural codes: effects of a shift between task rules

Interactions with neocortical memory systems may facilitate flexible information processing by hippocampus. We sought direct evidence for such memory influences by recording hippocampal neural responses to a change in cognitive strategy. Well-trained rats switched (within a single recording session) between the use of place and response strategies to solve a plus maze task. Maze and extramaze environments were constant throughout testing. Place fields demonstrated (in-field) firing rate and location-based reorganization [Leutgeb, S., Leutgeb, J. K., Barnes, C. A., Moser, E. I., McNaughton, B. L., & Moser, M. B. (2005). Independent codes for spatial and episodic memory in hippocampal neuronal ensembles. Science, 309, 619-623] after a task switch, suggesting that hippocampus encoded each phase of testing as a different context, or episode. The task switch also resulted in qualitative and quantitative changes to discharge that were correlated with an animal's velocity or acceleration of movement. Thus, the effects of a strategy switch extended beyond the spatial domain, and the movement correlates were not passive reflections of the current behavioral state. To determine whether hippocampal neural responses were unique, striatal place and movement-correlated neurons were simultaneously recorded with hippocampal neurons. Striatal place and movement cells exhibited a response profile that was similar, but not identical, to that observed for hippocampus after a strategy switch. Thus, retrieval of a different memory led both neural systems to represent a different context. However, hippocampus may play a special (though not exclusive) role in flexible spatial processing since correlated firing amongst cell pairs was highest when rats successfully switched between two spatial tasks. Correlated firing by striatal cell pairs increased following any strategy switch, supporting the view that striatum codes change in reinforcement contingencies.     

Acquisition of spatial knowledge in different urban areas: evidence from a survey analysis of adolescents

We herein explore the perception of the geographic environment and analyse the mechanisms that constrain the cognitive processing of spatial information in general. Our guiding theoretical background assumption is that the structure of the spatial environment is a cognitively robust and mutually constrained threefold system relating (1) cognitive topology (comprised of a path and place structure of spatial information and constrained by reference frame-based factors), (2) experience-based functional knowledge (including the effects of socio-economic factors, frequency and familiarity) and (3) linguistic representations (primarily encoded in the prepositional system of a natural language). Here, we focus on (2), i.e. the effect of functional knowledge on the process of acquiring spatial knowledge. We empirically tested adolescents aged 12–17 years to explore the interaction between frequency, familiarity and functional knowledge from a developmental point of view. The social factors we explore are precisely defined and parameterized in our results (exposure to a particular urban area, place of residence, gender, age and factors relating to the environmental and social quality of the local area). Our research shows that there are divergences between the so-called objective topology and the cognitive typology of the urban environment that are significantly constrained by intensity of interactions with environment, number of functionally significant places within particular area and age from a developmental perspective in terms of spatial knowledge acquisition.     

Visual search enhances subsequent mnemonic search

We examined how the performance of a visual search task while studying a list of to-be-remembered words affects subsequent memory for those words by humans. Previous research had suggested that episodic context encoding is facilitated when the study phase of a memory experiment requires, or otherwise encourages, a visual search for the to-be-remembered stimuli, and theta-band oscillations are more robust when animals are searching their environment. Moreover, hippocampal theta oscillations are positively correlated with learning in animals. We assumed that a visual search task performed during the encoding of words for a subsequent memory test would induce an exploratory state that would mimic the one that is induced in animals when performing exploratory activities in their environment, and that the encoding of episodic traces would be improved as a result. The results of several experiments indicated that the performance of the search task improved free recall, but the results did not extend to yes–no or forced choice recognition memory testing. We propose that visual search tasks enhance the encoding of episodic context information but do not enhance the encoding of to-be-remembered words.     

Episodic memory updating: The role of context familiarity

We previously demonstrated that spatial context is a powerful reminder that can trigger memory updating (Hupbach, Hardt, Gomez, & Nadel in Learning & Memory, 15, 574–579 2008). In the present study, we asked whether the familiarity of the spatial context modulates the role of spatial context as a reminder. Since context familiarity can be easily manipulated in children, we chose 5-year-olds as study participants. In two experiments, we demonstrated robust memory-updating effects in children. Spatial context triggered incorporation of new information into old memories only when the context was unfamiliar. In highly familiar spatial environments (children’s homes), spatial context did not initiate memory updating. Other reminders (the experimenter and a reminder question) became highly effective in familiar contexts. These findings shed further light on the specific conditions that trigger memory updating and support the view that the mechanisms underlying it are similar in children and adults.     

Effect of electric shock on rats' activity in familiar and unfamiliar environments

It is found that electric shock delivered before exposure to a Y-maze reduces the activity of rats whether the maze is familiar or unfamiliar. Increasing familiarity with the maze reduces activity for shocked and unshocked rats. It is argued that this finding presents difficulties for theories according to which exploratory behaviour depends on fear.     

The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward

The hippocampus is believed to play a role in processing information relative to the context in which emotionally salient experiences occur but evidence on the specific contribution of the hippocampal dentate gyrus (DG) to these processes is limited. Here, we have used two classical behavioral paradigms to study the participation of the dorsal DG in context-conditioned reward and context-conditioned fear. Rats received intra-hippocampal vehicle or colchicine injections (4 microg/microl solution; 0.2 microl injections at 10 sites) that damaged the DG but spared other hippocampal subfields. In the first experiment, we used a place conditioning procedure pairing cocaine exposure (20 mg/kg, i.p.) with a specific context and vehicle treatment with another. While rats with sham lesions exhibited preference for the cocaine-paired context following conditioning, rats with lesions of the DG showed no evidence of cocaine-induced place preference. In the second experiment, rats with sham or colchicine lesions received a foot shock in a given context and conditioned freezing was measured upon reexposure to the shock-paired context (2, 24, 48 and 96 h after conditioning). Rats with sham lesions exhibited high levels of conditioned freezing when exposed to the conditioning context but rats with lesions of the DG showed impaired conditioning, behaving as controls that had experienced shock in a different context. These observations indicate that the integrity of the DG is essential for establishing a coherent representation of the context to which emotional experiences, either hedonic or aversive, are bound.     

Parallel processing across neural systems: implications for a multiple memory system hypothesis

A common conceptualization of the organization of memory systems in brain is that different types of memory are mediated by distinct neural systems. Strong support for this view comes from studies that show double (or triple) dissociations between spatial, response, and emotional memories following selective lesions of hippocampus, striatum, and the amygdala. Here, we examine the extent to which hippocampal and striatal neural activity patterns support the multiple memory systems view. A comparison is made between hippocampal and striatal neural correlates with behavior during asymptotic performance of spatial and response maze tasks. Location- (or place), movement, and reward-specific firing patterns were found in both structures regardless of the task demands. Many, but not all, place fields of hippocampal and striatal neurons were similarly affected by changes in the visual and reward context regardless of the cognitive demands. Also, many, but not all, hippocampal and striatal movement-sensitive neurons showed significant changes in their behavioral correlates after a change in visual context, irrespective of cognitive strategy. Similar partial reorganization was observed following manipulations of the reward condition for cells recorded from both structures, again regardless of task. Assuming that representations that persist across context changes reflect learned information, we make the following conclusions. First, the consistent pattern of partial reorganization supports a view that the analysis of spatial, response, and reinforcement information is accomplished via an error-driven, or match-mismatch, algorithm across neural systems. Second, task-relevant processing occurs continuously within hippocampus and striatum regardless of the cognitive demands of the task. Third, given the high degree of parallel processing across allegedly different memory systems, we propose that different neural systems may effectively compete for control of a behavioral expression system. The strength of the influence of any one neural system on behavioral output is likely modulated by factors such as motivation, experience, or hormone status.     

Multiple context mere exposure: Examining the limits of liking

Recent evidence suggests that increased liking of exposed stimuli—a phenomenon known as the mere exposure effect—is dependent on experiencing the stimuli in the same context at exposure and test. Three experiments extended this work by examining the effect of presenting target stimuli in single and multiple exposure contexts. Target face stimuli were repeatedly paired with nonsense words, which took the role of contexts, across exposure. On test, the mere exposure effect was found only when the target face stimuli were presented with nonsense word cues (contexts) with which they had been repeatedly paired. The mere exposure effect was eliminated when exposure to target face stimuli with the nonsense word cues (contexts) was minimal, despite the overall number of exposures to the target face being equated across single- and multiple-context exposure conditions. The results suggest that familiarity of the relationship between stimuli and their context, not simply familiarity of the stimuli themselves, leads to liking. The finding supports a broader framework, which suggests that liking is partly a function of the consistency between past and present experiences with a target stimulus.     

The hippocampus, space, and viewpoints in episodic memory

A computational model of how single neurons in and around the rat hippocampus support spatial navigation is reviewed. The extension of this model, to include the retrieval from human long-term memory of spatial scenes and the spatial context of events is discussed. The model explores the link between spatial and mnemonic functions by supposing that retrieval of spatial information from long-term storage requires the imposition of a particular viewpoint. It is consistent with data relating to representational hemispatial neglect and the involvement of the mammillary bodies, anterior thalamus, and hippocampal formation in supporting both episodic recall and the representation of head direction. Some recent behavioural, neuropsychological, and functional neuroimaging experiments are reviewed, in which virtual reality is used to allow controlled study of navigation and memory for events set within a rich large-scale spatial context. These studies provide convergent evidence that the human hippocampus is involved in both tasks, with some lateralization of function (navigation on the right and episodic memory on the left). A further experiment indicates hippocampal involvement in retrieval of spatial information from a shifted viewpoint. I speculate that the hippocampal role in episodic recollection relates to its ability to represent a viewpoint moving within a spatial framework.     

Pre-training prevents context fear conditioning deficits produced by hippocampal NMDA receptor blockade

These experiments explore parallels between the neurobiological substrates of spatial and context learning. Male Long-Evans rats were employed in a context fear conditioning protocol that involved sequential acquisition and testing in two distinct contexts. Rats received three unsignaled footshocks in one context and were tested for context fear, measured as freezing, the next day. Four days later, the procedure was repeated in a different, distinct context. Rats received a hippocampal infusion of either the NMDA receptor antagonist 5-amino-phosphonovaleric acid (APV, 10 microg) or vehicle prior to training in each context. NMDA receptor blockade was effective in impairing context learning only in the first context. Context fear acquisition was not impaired by APV in the second context, indicating that pre-training (in the first context) mitigated the effects of APV. These data agree with those seen previously in the water maze, where pre-training prevented learning deficits produced by NMDA receptor blockade. The data thus suggest that the neurobiological substrates of context learning and place learning overlap.     

A simple neural network model of the hippocampus suggesting its pathfinding role in episodic memory retrieval

The goal of this work is to extend the theoretical understanding of the relationship between hippocampal spatial and memory functions to the level of neurophysiological mechanisms underlying spatial navigation and episodic memory retrieval. The proposed unifying theory describes both phenomena within a unique framework, as based on one and the same pathfinding function of the hippocampus. We propose a mechanism of reconstruction of the context of experience involving a search for a nearly shortest path in the space of remembered contexts. To analyze this concept in detail, we define a simple connectionist model consistent with available rodent and human neurophysiological data. Numerical study of the model begins with the spatial domain as a simple analogy for more complex phenomena. It is demonstrated how a nearly shortest path is quickly found in a familiar environment. We prove numerically that associative learning during sharp waves can account for the necessary properties of hippocampal place cells. Computational study of the model is extended to other cognitive paradigms, with the main focus on episodic memory retrieval. We show that the ability to find a correct path may be vital for successful retrieval. The model robustly exhibits the pathfinding capacity within a wide range of several factors, including its memory load (up to 30,000 abstract contexts), the number of episodes that become associated with potential target contexts, and the level of dynamical noise. We offer several testable critical predictions in both spatial and memory domains to validate the theory. Our results suggest that (1) the pathfinding function of the hippocampus, in addition to its associative and memory indexing functions, may be vital for retrieval of certain episodic memories, and (2) the hippocampal spatial navigation function could be a precursor of its memory function.     

Diversity within Spatial Cognition: Memory Processes Underlying Place Recognition

We conducted three experiments to explore distinct memory processes involved in remembering places in spatial environments. The results of all three experiments demonstrated the viability of the process-dissociation procedure for studying spatial cognition; that procedure yielded separate measures of the role of familiarity (implicit memory) and conscious recollection (explicit memory) in recognizing scenes along a previously viewed route of travel. Those measures were not affected by whether the participants viewed videotapes or also physically walked the route of travel. Increasing the delay between encoding and retrieval led to comparable effects for familiarity and conscious recollection (Experiment 1). In contrast, the adverse consequences of dividing attention during encoding were specific to conscious recollection; familiarity estimates were unaffected (Experiments 2 and 3). Overall, the results reinforced the viability of process dissociation as a vehicle for exploring diverse memory processes underlying place recognition.     

Contextual factors in neophobia and its habituation: The role of absolute and relative novelty

In four experiments we investigated the role of contextual cues in the habituation of neophobia in rats. Experiment 1 showed that the consumption of a novel flavour increased across a series of presentations in one context (A) but fell when the flavour was subsequently presented in a second, novel, context (B). In Experiments 2 and 3, subjects again received exposure to a flavour in context A, but also were familiarized with the test context, B. These subjects consumed the flavour with equal readiness, whether it was presented in Context A or in Context B at test. Experiment 4 replicated the results of Experiment 1 and also showed that the consumption of a novel flavour was not influenced by whether it was presented in a novel or a familiar context. Several mechanisms by which the novelty or familiarity of the context might interact with the novelty or familiarity of the flavour were discussed.     

Revisiting places passed: Sensitization of exploratory activity in rats with hippocampal lesions

We examined the involvement of the hippocampus in short-term changes in exploratory behaviour in an open field (Experiment 1) and experimental contexts (Experiment 2). In Experiment 1, rats with excitotoxic lesions of the hippocampus were more likely to revisit recently visited zones within the open field than were control rats. Similarly, in Experiment 2 rats with hippocampal lesions showed greater exploration of a context that they had recently explored than a context that they had less recently explored. This short-term sensitization effect was not evident in control rats. These findings are consistent with the suggestion that the recent presentation of a stimulus has two opposing effects on behaviour, sensitization, and habituation, and that hippocampal lesions disrupt the short-term process responsible for habituation, but not that responsible for sensitization.     

Learning strategy selection in the water maze and hippocampal CREB phosphorylation differ in two inbred strains of mice

Learning strategy selection was assessed in two different inbred strains of mice, C57BL/6 and DBA/2, which are used for developing genetically modified mouse models. Male mice received a training protocol in a water maze using alternating blocks of visible and hidden platform trials, during which mice escaped to a single location. After training, mice were required to choose between the spatial location where the platform had been during training (a place strategy) and a visible platform presented in a new location (a cued/response strategy). Both strains of mice had similar escape performance on the visible and hidden platform trials during training. However, in the strategy preference test, C57BL/6 mice selected a place strategy significantly more often than DBA/2 mice. Because much evidence implicates the hippocampus and striatum as important neural substrates for spatial/place and cued/response learning, respectively, the engagement of the hippocampus was then assessed after either place or cue training by determining levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) in these two mouse strains. Results revealed that hippocampal CREB levels in both strains of mice were significantly increased after place in comparison to cued training. However, the relation of hippocampal pCREB levels to training was strain dependent; pCREB was significantly higher in C57BL/6 mice than in DBA/2 mice after place training, while hippocampal pCREB levels did not differ between strains after cued training. These findings indicate that pCREB, specifically associated with place/spatial training, is closely tied to differences in spatial/place strategy preference between C57BL/6 and DBA/2 mice.     

Effects of simple- and complex-place contexts in the multiple-context paradigm

In four experiments, a total of 384 undergraduates incidentally learned a list of 24 nouns twice in the same context (same-context repetition) or different contexts (different-context repetition). Free recall was measured in a neutral context. Experiments 1, 2, and 3 used a context repetition (same- or different-context repetition) × inter-study and retention intervals (10 min or 1 day) between-participants design. Context was manipulated by the combination of place, social environment, and encoding task (Experiment 1), place and social environment (Experiment 2), or place alone (Experiment 3). Experiment 4 used a context repetition × type of context (context manipulated by place or by place, social environment, and encoding task) between-participants design, with a 10-min inter-study interval and a one-day retention interval. The present results indicate that the determinant of the superiority of same- or different-context repetition in recall is the type of context. Implications of the results were discussed.     

Revisiting places passed: sensitization of exploratory activity in rats with hippocampal lesions

We examined the involvement of the hippocampus in short-term changes in exploratory behaviour in an open field (Experiment 1) and experimental contexts (Experiment 2). In Experiment 1, rats with excitotoxic lesions of the hippocampus were more likely to revisit recently visited zones within the open field than were control rats. Similarly, in Experiment 2 rats with hippocampal lesions showed greater exploration of a context that they had recently explored than a context that they had less recently explored. This short-term sensitization effect was not evident in control rats. These findings are consistent with the suggestion that the recent presentation of a stimulus has two opposing effects on behaviour, sensitization, and habituation, and that hippocampal lesions disrupt the short-term process responsible for habituation, but not that responsible for sensitization.