A comparison and evaluation of the predictions of relational and conjunctive accounts of hippocampal function

Relational and conjunctive memory theory each postulate that the hippocampus participates in the formation of long-term memory representations comprised of associations between multiple elements. The goals of the current work were to clarify and contrast these theories by outlining the nature of the representations that are spared vs. impaired following hippocampal damage according to each theoretical perspective. Relational theory predicts that hippocampal lesions will impair performance on tasks that require the formation of new long-term representations in which distinct elements must be regarded in relation to all other elements. Representations that remain intact despite hippocampal damage include separate representations of distinct individual elements or multiple stimuli fused into a static "blend" such as several elements viewed from one vantage point. Additionally, the relational account predicts that rapid incidental online processing of the relations can be achieved through structures other than the hippocampus, but this information will not be stored. In contrast, conjunctive theory predicts that hippocampal damage will impair the rapid formation of unitary representations that contain features of elements and their relative relationships bound in an inflexible manner. Deficits in the rapid formation of these conjunctive representations result in impaired performance on tasks that require rapid incidental stimulus binding. However, intact formation of conjunctive representations can occur over multiple trials in the service of problem solving. Using these theoretical frameworks, recent findings from the human and nonhuman animal literature are reexamined in order to determine whether one theory better accounts for current findings. We discuss empirical studies that serve as "critical experiments" in addressing the relational vs. conjunctive debate, and find that the predictions of relational theory are supported by existing findings over those from the conjunctive account.     

Systematic comparison of the effects of hippocampal and fornix-fimbria lesions on acquisition of three configural discriminations

The effects of lesions to the hippocampal system on acquisition of three different configural tasks by rats were tested. Lesions of either the hippocampus (kainic acid/colchicine) or fornix-fimbria (radiofrequency current) were made before training. After recovery from surgery, rats were trained to discriminate between simple and compound-configural cues that signaled the availability or nonavailability of food when a bar was pressed. When positive cues were present, one food pellet could be earned by pressing a lever after a variable time had elapsed. The trial terminated on food delivery (variable interval 15 s). This procedure eliminates some possible alternative explanations of the results of previous experiments on configural learning. Hippocampal lesions increased rates of responding and retarded acquisition of a negative patterning task (A⁺, B⁺, AB⁻); using a ratio measure of discrimination performance these lesions had a milder retarding effect on a biconditional discrimination (AX⁺, AY⁻, BY⁺, BX⁻), and they had no effect on a conditional context discrimination (X: A⁺, B⁻; Y: A⁻, B⁺). Fornix-fimbria lesions did not affect acquisition of any of these tasks but increased rates of responding. The results suggest that several task parameters determine the involvement of the hippocampus in configural learning; however, all tasks tested can also be learned to some extent in the absence of an intact hippocampal system, presumably by other learning/memory systems that remain intact following surgery. The lack of effect of fornix-fimbria lesions on any of these tasks suggests that retrohippocampal connections with other brain areas may mediate hippocampal contributions to the learning of some configural tasks. An analysis of these results and of experiments on spatial learning situations suggests that involvement of the hippocampus is a function of the degree to which correct performance depends on a knowledge of relationships among cues in a situation. Hippocampus 7:371–388, 1997. © 1997 Wiley-Liss, Inc.     

Configural association theory and the hippocampal formation: An appraisal and reconfiguration

Sutherland and Rudy ([1989] Psychobiology 17:129–144) proposed that the hippocampal system is critical to normal learning and memory because of its function as the central part of a configural association system. This system constructs a unique representation of the joint occurrence of the independent elements of a compund. There is evidence consistent with the theory's predictions, however, there also are data that unambiguously demonstrate that, under some conditions, animals lacking an intact hippocampal system acquire configural associations. Thus, Sutherland and Rudy's fundamental assumption cannot be correct. To integrate the supporting and contradictory data, we propose two simple modifications of our position: (1) The critical neural system for configural associations is in cortical circuitry outside the hippocampus, and (2) the output from the hippocampal formation contributes to configural processing by selectively enhancing, thereby making more salient, cortical units representing stimulus conjunctions. This enhancement has two important effects: (1) It decreases the similarity between the configural units representing the co-occurrence of cues and the units representing the cues, and (2) it increases the rate at which the configural units can acquire associative strength. The modified theory explains why damage to the hippocampal formation only impairs learning on a subset of nonlinear discrimination problems. It also integrates recent data on the effects of hippocampal formation damage on conditioning involving context cues and makes novel predictions about performance on nonlinear discrimination problems and place learning. © 1995 Wiley-Liss, Inc.     

Computational models of the hippocampal region: implications for prediction of risk for Alzheimer's disease in non-demented elderly

We have pursued an interdisciplinary research program to develop novel behavioral assessment tools for evaluating specific memory impairments following damage to the medial temporal lobe, including the hippocampus and associated structures that show pathology early in the course of Alzheimer's disease (AD). Our approach uses computational models to identify the functional consequences of hippocampal-region damage, leading to testable predictions in both rodents and humans. Our modeling argues that hippocampal-region dysfunction may selectively impair the ability to generalize when familiar information is presented in novel recombinations. Previous research has shown that specific reductions in hippocampal volume in non-demented elderly individuals correlate with future development of AD. In two previous studies, we tested non-demented elderly with and without mild hippocampal atrophy (HA) on stimulus-response learning tasks. Individuals with and without HA could learn the initial information, but the HA group was selectively impaired on transfer tests where familiar features and objects were recombined. This suggests that such generalization deficits may be behavioral markers of HA, and an early indicator of risk for subsequent cognitive decline. Converging support for the relevance of these tasks to aging and Alzheimer's disease comes from our recent fMRI studies of individuals with mild cognitive impairment (MCI). Activity in the hippocampus declines with progressive training on these tasks, suggesting that the hippocampus is important for learning new stimulus representations that support subsequent transfer. Individuals with HA may be able to learn, but in a more hippocampal-independent fashion that does not support later transfer. Ultimately, this line of research could lead to a novel battery of behavioral tests sensitive to very mild hippocampal atrophy and risk for decline to AD, allowing early diagnosis and also allowing researchers to test new Alzheimer's drugs that target individuals in the earliest stages of the disease - before significant cognitive decline. A new mouse version of one of our tasks shows promise for translating these paradigms into rodents, allowing for future studies of therapeutic interventions in transgenic mouse models of AD.     

Functional dissociation between fornix and hippocampus in spatial conditional learning

Do lesions of the fornix or the hippocampus impair the performance of spatial conditional associative learning tasks, and to what extent does damage to these brain structures result in comparable deficits in this type of spatial behavior? The available evidence is not clear. In the present study, rats with lesions of the fornix, hippocampus, and normal control animals were trained on two spatial–visual conditional learning tasks in which they had to form arbitrary associations between visual stimuli and the context in which these stimuli were embedded. In one condition, rats were required to choose stimulus X in place A and stimulus Y in place B, and there was no overlap in the contents of the two scenes. In the other condition, the animal approached the same scene from two different directions and had to select stimulus X when the scene was viewed from perspective A and to select stimulus Y when the scene was viewed from perspective B. Rats with fornix transection were able to learn both conditional tasks at a rate comparable to that of normal control animals, but rats with hippocampal damage were severely impaired under both conditions. The findings extend the range of tasks known to be sensitive to damage of the hippocampus. In addition, the results argue that the fornix is not necessary for the acquisition of certain spatial conditional learning tasks and that this brain structure cannot be used as an indicator of hippocampal dysfunction under all learning situations. © 2007 Wiley‐Liss, Inc.     

Hippocampal neuronal position selectivity remains fixed to room cues only in rats alternating between place navigation and beacon approach tasks

To study the relationship between brain representations and behaviour, we recorded hippocampal neuronal activity in rats repeatedly alternating between two different tasks on a circular platform with four reward boxes along the edge. In the beacon approach task, rewards were provided only at the pair of diametrically opposite boxes that was illuminated. In the place navigation task, rewards were available only at the boxes positioned near the north-east and south-west corners of the room. Performance levels were high and rats rapidly reoriented to changes in lamp cues in the beacon approach task. Neuropsychological studies show that rats with hippocampal lesions readily employ beacon approach strategies, while place navigation is severely impaired. Previous studies suggested that the neurons might change their behavioural correlates as the rat performed the respective tasks. However, of 34 hippocampal 'place cells' recorded, all showed position selectivity fixed with respect to room cues, even in the beacon approach task where coding the position of the rat in the room was of no use for locating rewards. Whether or not hippocampal signals are actually employed for ongoing behaviour would then be decided by structures downstream from the hippocampus. If this is the case, then the 'counterproductive' room referred place-related discharges in the beacon approach task would be a background representation. This would provide support for proposals of multiple memory systems underlying different types of information processing and contrasts with the popular notion that local neuronal activity levels are selectively increased to the degree that the brain region is required for the ongoing function.     

Hippocampal lesions can enhance discrimination learning despite normal sensitivity to interference from incidental information

Spatial properties of stimuli are sometimes encoded even when incidental to the demands of a particular learning task. Incidental encoding of spatial information may interfere with learning by (i) causing a failure to generalize learning between trials in which a cue is presented in different spatial locations and (ii) adding common spatial features to stimuli that predict different outcomes. Hippocampal lesions have been found to facilitate acquisition of certain tasks. This facilitation may occur because hippocampal lesions impair incidental encoding of spatial information that interferes with learning. To test this prediction mice with lesions of the hippocampus were trained on appetitive simple simultaneous discrimination tasks using inserts in the goal arms of a T-maze. It was found that hippocampal lesioned mice were facilitated at learning the discriminations, but they were sensitive to changes in spatial information in a manner that was similar to control mice. In a second experiment it was found that both control and hippocampal lesioned mice showed equivalent incidental encoding of egocentric spatial properties of the inserts, but both groups did not encode the allocentric information. These results demonstrate that mice show incidental encoding of egocentric spatial information that decreases the ability to solve simultaneous discrimination tasks. The normal egocentric spatial encoding in hippocampal lesioned mice contradicts theories of hippocampal function that suggest that the hippocampus is necessary for incidental learning per se, or is required for modulating stimulus representations based on the relevancy of information. The facilitated learning suggests that the hippocampal lesions can enhance learning of the same qualitative information as acquired by control mice.     

Cues that hippocampal place cells encode: Dynamic and hierarchical representation of local and distal stimuli

Hippocampal place fields were recorded as rats explored a four-arm radial maze surrounded by curtains holding distal stimuli and with distinct local tactile, olfactory, and visual cues covering each arm. Systematic manipulations of the individual cues and their interrelationships showed that different hippocampal neurons encoded individual local and distal cues, relationships among cues within a stimulus set, and the relationship between the local and distal cues. Double rotation trials, which maintained stimulus relationships within distal and local cue sets, but altered the relationship between them, often changed the responses of the sampled neural population and produced new representations. After repeated double rotation trials, the incidence of new representations increased, and the likelihood of a simple rotation with one of the cue sets diminished. Cue scrambling trials, which altered the topological relationship within the local or distal stimulus set, showed that the cells that followed one set of controlled stimuli responded as often to a single cue as to the constellation. These cells followed the single cue when the stimulus constellation was scrambled, but often continued firing in the same place when the stimulus was removed or switched to respond to other cues. When the maze was surrounded by a new stimulus configuration, all of the cells either developed new place fields or stopped firing, showing that the controlled stimuli had persistent and profound influence over hippocampal neurons. Together, the results show that hippocampal neurons encode a hierarchical representation of environmental information. Hippocampus 1997;7:624–642. © 1997 Wiley-Liss, Inc.     

Environment-spatial conditional learning in rats with selective lesions of medial septal cholinergic neurons

Cholinergic medial septal neurons may regulate several aspects of hippocampal function, including place field stability and spatial working memory. Monkeys with damage to septal cholinergic neurons are impaired in visual-spatial conditional learning tasks; however, this candidate function of septal cholinergic neurons has not been studied extensively in the rat. In the present study, rats with selective lesions of cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB), made with 192 IgG-saporin, were tested on a conditional associative learning task. In this task, which we term "environment-spatial" conditional learning, the correct location of a spatial response depended on the array of local environmental cues. MS/VDB-lesioned rats were impaired when the two parts of the conditional problem were presented concurrently, but not when one environment had been learned before the full conditional problem was presented. Our findings suggest that cholinergic MS/VDB neurons participate in some aspects of conditional associative learning in rats. They may also shed light on the involvement of cholinergic projections to the hippocampus in modulating and remodeling hippocampal spatial representations.     

Conditioning and cognition

Animals' abilities to use internal representations of absent objects to guide adaptive behavior and acquire new information, and to represent multiple spatial, temporal, and object properties of complex events and event sequences, may underlie many aspects of human perception, memory, and symbolic thought. In this review, two classes of simple associative learning tasks that address these core cognitive capacities are discussed. The first set, including reinforcer revaluation and mediated learning procedures, address the power of Pavlovian conditioned stimuli to gain access, through learning, to representations of upcoming events. The second set of investigations concern the construction of complex stimulus representations, as illustrated in studies of contextual learning, the conjunction of explicit stimulus elements in configural learning procedures, and recent studies of episodic-like memory. The importance of identifying both cognitive process and brain system bases of performance in animal models is emphasized.     

The Cerebellum Is Involved in Reward-based Reversal Learning

The cerebellum has recently been discussed in terms of a possible involvement in reward-based associative learning. To clarify the cerebellar contribution, eight patients with focal vascular lesions of the cerebellum and a group of 24 healthy subjects matched for age and IQ were compared on a range of different probabilistic outcome-based associative learning tasks, assessing acquisition, reversal, cognitive transfer, and generalization as well as the effect of reward magnitude. Cerebellar patients showed intact acquisition of stimulus contingencies, while reward-based reversal learning was significantly impaired. In addition, the patients showed slower acquisition of new stimulus contingencies in a second reward-based learning task, which might reflect reduced carry-over effects. Reward magnitude affected learning only during initial acquisition, with better learning on trials with high rewards in patients and control subjects. Overall, the findings suggest that the cerebellum is implicated in reversal learning as a dissociable component of reward-based learning.     

Hippocampal BOLD response during category learning predicts subsequent performance on transfer generalization

To test a prediction of our previous computational model of cortico‐hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI‐adapted category‐learning task that has two phases, an initial phase in which associations are learned through trial‐and‐error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning‐related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands. Hum Brain Mapp 35:3122–3131, 2014. © 2013 Wiley Periodicals, Inc .     

Impairments in spatial learning and memory: ethanol, allopregnanolone, and the hippocampus

Acute ethanol administration impairs performance in many cognitive tasks that are dependent on hippocampal function. For example, acute ethanol administration produces dose-dependent impairments in spatial learning. Ethanol also decreases the spatial specificity of hippocampal place cells. Such findings raise the possibility that ethanol affects learning and memory by altering, either directly or indirectly, neuronal activity in the hippocampus and related structures.Acute ethanol administration induces a dose- and time-dependent increase in brain concentration of the neuroactive steroid allopregnanolone. Allopregnanolone is a potent GABA_A receptor agonist and produces effects similar to the effects produced by ethanol. Blockade of de novo biosynthesis of allopregnanolone alters many of ethanol's effects including ethanol-induced suppression of spontaneous activity in medial septum/diagonal band of Broca neurons and hippocampal pyramidal neurons. These findings suggest that ethanol-induced increases in allopregnanolone levels might play a central role in the effects of acute ethanol on cognitive processing and hippocampal function.The impact of ethanol on spatial cognitive processing and hippocampal function will be reviewed. In addition, the possibility that ethanol-induced changes in neuroactive steroid levels contribute to the impact of ethanol on spatial learning and hippocampal function will be explored.     

Interpreting hippocampal function as recoding and forecasting.

A model of hippocampal function, centered on region CA3, reproduces many of the cognitive and behavioral functions ascribed to the hippocampus. Where there is precise stimulus control and detailed quantitative data, this model reproduces the quantitative behavioral results. Underlying the model is a recoding conjecture of hippocampal computational function. The expanded conjecture includes a special role for randomization and, as recoding progresses with experience, the occurrence of sequence learning and sequence compression. These functions support the putative higher-order hippocampal function, i.e. production of representations readable by a linear decoder and suitable for both neocortical storage and forecasting. Simulations confirm the critical importance of randomly driven recoding and the neurocognitive relevance of sequence learning and compression. Two forms of sequence compression exist, on-line and off-line compression: both are conjectured to support neocortical encoding of context and declarative memory as described by .     

Hippocampal representation in place learning

The generality of the place-learning impairment associated with hippocampal system damage was challenged using methods of training that permitted subjects to form an individual association between the place of escape and a particular navigational route in an open-field water maze. Both normal rats and rats with fornix lesions (FX rats) acquired this task rapidly, although FX rats were slightly slower in achieving minimum escape latencies. In postcriterion testing, FX rats occasionally made near misses but, more often, their escape performance was indistinguishable from that of intact rats. Results from a variety of probe tests indicated that FX rats, like normal rats, had based their performance on a representation of multiple distal cues but their representation, unlike that of normal rats, was inflexible in that it could not be used to guide performance when the cues or starting position were altered. These results parallel those from other studies of hippocampal function in animals and humans: The learning deficit consequent to hippocampal system damage (1) is not specific to a particular category of learning materials, but is dependent on the representational demands of the task; (2) is observed when task demands encourage a representation based on relations among multiple cues, but not when the task encourages adaptation to an individual (or compound) stimulus; (3) spares acquisition of fundamental procedures needed to perform the task; and (4) impairs the flexible use of learned information in tests other than repetition of the learning experience.     

Transitive behavior in hippocampal-lesioned pigeons

The hippocampus of birds and mammals is critical for the learning of map-like memory representations of environmental space. It has been suggested that the hippocampus of rats also participates in non-spatial relational learning, including the learning of non-spatial transitive relationships among odor stimuli [Bunsey and Eichenbaum, Nature 1996]. Although transitive-like learning has been demonstrated in a variety of vertebrate species, from a comparative perspective the role of the hippocampus in this form of learning has not been tested in other amniote groups. We trained control and hippocampal-lesioned homing pigeons on a series of visual, non-spatial, go/no-go conditional discriminations and then tested them on novel transitivity probe trials. The hippocampal-lesioned pigeons were as successful as control pigeons in responding appropriately to correct and incorrect transitivity pairs. The finding that the homing pigeon hippocampal formation is not necessary for solving this serial, conditional discrimination task is important for further understanding hippocampal function across species, and represents one of the few studies that have attempted to localize a brain region responsible for the phenomenon of transitive behavior learning.     

Association rules for rat spatial learning: The importance of the hippocampus for binding item identity with item location

Three cohorts of rats with extensive hippocampal lesions received multiple tests to examine the relationships between particular forms of associative learning and an influential account of hippocampal function (the cognitive map hypothesis). Hippocampal lesions spared both the ability to discriminate two different digging media and to discriminate two different room locations in a go/no‐go task when each location was approached from a single direction. Hippocampal lesions had, however, differential effects on a more complex task (biconditional discrimination) where the correct response was signaled by the presence or absence of specific cues. For all biconditional tasks, digging in one medium (A) was rewarded in the presence of cue C, while digging in medium B was rewarded in the presences of cue D. Such biconditional tasks are “configural” as no individual cue or element predicts the solution (AC+, AD?, BD+, and BC?). When proximal context cues signaled the correct digging choice, biconditional learning was seemingly unaffected by hippocampal lesions. Severe deficits occurred, however, when the correct digging choice was signaled by distal room cues. Also, impaired was the ability to discriminate two locations when each location was approached from two directions. A task demand that predicted those tasks impaired by hippocampal damage was the need to combine specific cues with their relative spatial positions (“structural learning”). This ability makes it possible to distinguish the same cues set in different spatial arrays. Thus, the hippocampus appears necessary for configural discriminations involving structure, discriminations that potentially underlie the creation of cognitive maps. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Differential contributions of hippocampus, amygdala and perirhinal cortex to recognition of novel objects, contextual stimuli and stimulus relationships

This study examined contributions of the hippocampus, amygdala and perirhinal cortex to memory. Rats performed a cover task, and changes to stimulus identity or relationships were used to test incidental memory. Rats with hippocampal damage showed deficient responses to relationship changes, but demonstrated knowledge of the position and identity of the target object. They over-focused on the most predictive stimuli, and failed to acquire associations including surrounding cues. Rats with amygdala damage responded to changes involving distal stimuli, and showed deficient responses to novel objects and object relationships. These rats may be highly reliant on relational representations, resulting in a reduced salience for individual novel stimuli. Rats with perirhinal damaged responded to novel stimulus relationships and distal cues, but showed deficient responses to novel objects, suggesting that changes in identity had reduced salience. Implications for declarative and conjunctive hippocampal theories are discussed.     

The role of the hippocampus in generalizing configural relationships

The hippocampus has been implicated in integrating information across separate events in support of mnemonic generalizations. These generalizations may be underpinned by processes at both encoding (linking similar information across events) and retrieval (“on‐the‐fly” generalization). However, the relative contribution of the hippocampus to encoding‐ and retrieval‐based generalizations is poorly understood. Using fMRI in humans, we investigated the hippocampal role in gradually learning a set of spatial discriminations and subsequently generalizing them in an acquired equivalence task. We found a highly significant correlation between individuals’ performance on a generalization test and hippocampal activity during the test, providing evidence that hippocampal processes support on‐the‐fly generalizations at retrieval. Within the same hippocampal region there was also a correlation between activity during the final stage of learning (when all associations had been learnt but no generalization was required) and subsequent generalization performance. We suggest that the hippocampus spontaneously retrieves prior events that share overlapping features with the current event. This process may also support the creation of generalized representations during encoding. These findings are supportive of the view that the hippocampus contributes to both encoding‐ and retrieval‐based generalization via the same basic mechanism; retrieval of similar events sharing common features. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.