Interplay of the long axis of the hippocampus and ventromedial prefrontal cortex in schema‐related memory retrieval

When new information is relevant to prior knowledge or schema, it can be learned and remembered better. Rodent studies have suggested that the hippocampus and ventromedial prefrontal cortex (vmPFC) are important for processing schema‐related information. However, there are inconsistent findings from human studies on the involvement of the hippocampus and its interaction with the vmPFC in schema‐related memory retrieval. To address these issues, we used a human analog of the rodent spatial schema task to compare brain activity during immediate retrieval of paired associations (PAs) in schema‐consistent and schema‐inconsistent conditions. The results showed that the anterior hippocampus was more involved in retrieving PAs in the schema‐consistent condition than in the schema‐inconsistent condition. Connectivity analyses showed that the anterior hippocampus had stronger coupling with the vmPFC when the participants retrieved newly learned PAs successfully in the schema‐consistent (vs. schema‐inconsistent) condition, whereas the coupling of the posterior hippocampus with the vmPFC showed the opposite. Taken together, the results shed light on how the long axis of the hippocampus and vmPFC interact to serve memory retrieval via different networks that differ by schema condition.     

Expression of c-fos in the main olfactory bulb of neonatal rabbits in response to garlic as a novel and conditioned odour

Expression of c-Fos was examined in the olfactory bulbs of 3-day-old rabbits after they had been presented with the odour of garlic as a novel stimulus, as a learned odour, or during conditioning, and this expression compared with baseline levels in non-stimulated controls. Exposure to garlic odour resulted in substantial and widespread increases in c-Fos expression in the olfactory bulbs of all animals. However, although conditioned pups showed a specific behavioural response to the learned garlic odour, neither the amount nor pattern of c-Fos expression differed compared to pups exposed to garlic as a novel odour. The odour-induced expression of c-Fos was not well localised, although there was a significant increase in the number of granule cells expressing c-Fos in the ventrolateral region of the bulb. These results support previous reports that the response to odours in the olfactory bulb of new-born animals is not as spatially distinct as that in adults. Nevertheless, the immature olfactory system of these young animals is clearly capable of very specific odour learning.     

γ-Aminobutyric acid receptor A-mediated inhibition in the honeybee's antennal lobe is necessary for the formation of configural olfactory percepts

Complex odours often possess perceptual qualities that are distinct from their components. Previous studies in humans, rodents, and insects indicate that the perception of complex odour blends depends on the concentration of the components and the mixture's complexity. However, we know relatively little about the way that an odour mixture 'gestalt' is produced by the olfactory system. Here, using an assay for olfactory conditioning in the honeybee (Apis mellifera), we examine the role of γ-aminobutyric acid receptor A (GABA(A) )-ergic inhibition within the olfactory primary relay, the antennal lobe, in the formation of a unique odour percept for complex odours. We found that honeybees perceive odour mixtures as configural stimuli when the mixtures were of low concentration and when they were composed of more than two odorants. When GABA(A) receptors were disrupted using the antagonist, picrotoxin, injected directly into the antennal lobe, we observed that bees no longer perceived the mixture as a configural stimulus. Our results imply that synchronization of antennal lobe projection neurons mediated by GABA(A) receptors is the mechanism responsible for the formation of unique olfactory percepts for complex odours.     

Hippocampus,delay discounting,and vicarious trial‐and‐error

In decision‐making, an immediate reward is usually preferred to a delayed reward, even if the latter is larger. We tested whether the hippocampus is necessary for this form of temporal discounting, and for vicarious trial‐and‐error at the decision point. Rats were trained on a recently developed, adjustable delay‐discounting task (Papale et al. (2012) Cogn Affect Behav Neurosci 12:513–526), which featured a choice between a small, nearly immediate reward, and a larger, delayed reward. Rats then received either hippocampus or sham lesions. Animals with hippocampus lesions adjusted the delay for the larger reward to a level similar to that of sham‐lesioned animals, suggesting a similar valuation capacity. However, the hippocampus lesion group spent significantly longer investigating the small and large rewards in the first part of the sessions, and were less sensitive to changes in the amount of reward in the large reward maze arm. Both sham‐ and hippocampus‐lesioned rats showed a greater amount of vicarious trial‐and‐error on trials in which the delay was adjusted. In a nonadjusting version of the delay discounting task, animals with hippocampus lesions showed more variability in their preference for a larger reward that was delayed by 10 s compared with sham‐lesioned animals. To verify the lesion behaviorally, rat were subsequently trained on a water maze task, and rats with hippocampus lesions were significantly impaired compared with sham‐lesioned animals. The findings on the delay discounting tasks suggest that damage to the hippocampus may impair the detection of reward magnitude. © 2014 Wiley Periodicals, Inc.     

Biological complexity and adaptability of simple mammalian olfactory memory systems

Chemosensory systems play vital roles in the lives of most mammals, including the detection and identification of predators, as well as sex and reproductive status and the identification of individual conspecifics. All of these capabilities require a process of recognition involving a combination of innate (kairomonal/pheromonal) and learned responses. Across very different phylogenies, the mechanisms for pheromonal and odour learning have much in common. They are frequently associated with plasticity of GABA-ergic feedback at the initial level of processing the chemosensory information, which enhances its pattern separation capability. Association of odourant features into an odour object primarily involves anterior piriform cortex for non-social odours. However, the medial amygdala appears to be involved in both the recognition of social odours and their association with chemosensory information sensed by the vomeronasal system. Unusually not only the sensory neurons themselves, but also the GABA-ergic interneurons in the olfactory bulb are continually being replaced, with implications for the induction and maintenance of learned chemosensory responses.     

Cerebral lateralization of olfactory-mediated affective processes in rats

To determine whether processing of information is lateralized in the brain of non-human mammalian species, rats that had undergone ablation of the left or right olfactory bulb were compared to sham-operated animals and to bilaterally bulbectomized animals in their response to emotionally positive or negative social odours. Left-bulbectomized rats were impaired in their behavioural reaction but not in their hormonal response to an odour from a stressed conspecific. They fully retained, however, their ability to recognize a nonstressed juvenile conspecific on the basis of its olfactory characteristics. These results suggest that hemispheric asymmetries develop in mammals not for recognition of emotional stimuli but for association of emotional experiences with appropriate adaptive behaviour.     

Do age differences in odour memory depend on differences in verbal memory?

Studies of human odour memory have in most cases been obscured by the experimental designs utilised, in which verbal memory played a crucial role in the subjects' performance. Previously, attempts have been made to minimise verbal mediation in the assessment of odour memory by the use of incidental or implicit learning, which is how odours are learned in everyday life; it is still under debate whether this form of learning is age-dependent or not. In this experiment we make use of very uncommon odours and show that incidental learning of odours is as good in elderly people as in the young, whereas intentional learning is better in young people.     

Long‐term effects of neonatal hippocampal lesions on novelty preference in monkeys

In a recent longitudinal study to assess the development of incidental recognition memory processes in monkeys, we showed that the effects of neonatal hippocampal lesions did alter incidental recognition memory only when the animals reached the juvenile period (Zeamer et al., 2010 ). The current follow‐up study tested whether this incidental memory loss was long‐lasting, i.e., present in adulthood, or only transitory, due to functional compensation with further brain maturation. The same animals with neonatal hippocampal lesions and their sham‐operated controls were re‐tested in the visual paired‐comparison task when they reached adulthood (48 months). The results demonstrated that, at least for easily discriminable color pictures of objects, the involvement of the hippocampus was only transitory, given that when re‐tested as adults, animals with neonatal hippocampal lesions performed as well as sham‐operated controls at all delays. Yet, significant recognition memory impairment was re‐instated when the discriminability of the stimuli was made more difficult (black/white pictures of similar objects). The data demonstrate profound functional remodeling within the hippocampus and its interactions with different medial temporal lobe structures from the juvenile period to adulthood, which is substantiated by a parallel morphological maturation of hippocampal intrinsic circuits (Lavenex et al., 2007a ; Jabès et al., 2011 ). © 2013 Wiley Periodicals, Inc.     

Measuring risk‐taking in mice: balancing the risk between seeking reward and danger

Assessing risk is an essential part of human behaviour and may be disrupted in a number of psychiatric conditions. Currently, in many animal experimental designs the basis of the potential ‘risk’ is loss or attenuation of reward, which fail to capture ‘real‐life’ risky situations where there is a trade‐off between a separate cost and reward. The development of rodent tasks where two separate and conflicting factors are traded against each other has begun to address this discrepancy. Here, we discuss the merits of these risk‐taking tasks and describe the development of a novel test for mice – the ‘predator‐odour risk‐taking’ task. This paradigm encapsulates a naturalistic approach to measuring risk‐taking behaviour where mice have to balance the benefit of gaining a food reward with the cost of exposure to a predator odour using a range of different odours (rat, cat and fox). We show that the ‘predator‐odour risk‐taking’ task was sensitive to the trade‐off between cost and benefit by demonstrating reduced motivation to collect food reward in the presence of these different predator odours in two strains of mice and, also, if the value of the food reward was reduced. The ‘predator‐odour risk‐taking’ task therefore provides a strong platform for the investigation of the genetic substrates of risk‐taking behaviour using mouse models, and adds a further dimension to other recently developed rodent tests.     

Early age‐dependent impairments of context‐dependent extinction learning,object recognition,and object‐place learning occur in rats

The hippocampus is vulnerable to age‐dependent memory decline. Multiple forms of memory depend on adequate hippocampal function. Extinction learning comprises active inhibition of no longer relevant learned information concurrent with suppression of a previously learned reaction. It is highly dependent on context, and evidence exists that it requires hippocampal activation. In this study, we addressed whether context‐based extinction as well as hippocampus‐dependent tasks, such as object recognition and object‐place recognition, are equally affected by moderate aging. Young (7‐8 week old) and older (7‐8 month old) Wistar rats were used. For the extinction study, animals learned that a particular floor context indicated that they should turn into one specific arm (e.g., left) to receive a food reward. On the day after reaching the learning criterion of 80% correct choices, the floor context was changed, no reward was given and animals were expected to extinguish the learned response. Both, young and older rats managed this first extinction trial in the new context with older rats showing a faster extinction performance. One day later, animals were returned to the T‐maze with the original floor context and renewal effects were assessed. In this case, only young but not older rats showed the expected renewal effect (lower extinction ratio as compared to the day before). To assess general memory abilities, animals were tested in the standard object recognition and object‐place memory tasks. Evaluations were made at 5 min, 1 h and 7 day intervals. Object recognition memory was poor at short‐term and intermediate time‐points in older but not young rats. Object‐place memory performance was unaffected at 5 min, but impaired at 1 h in older but not young rats. Both groups were impaired at 7 days. These findings support that not only aspects of general memory, but also context‐dependent extinction learning, are affected by moderate aging. This may reflect less flexibility in revising hard‐wired knowledge or reduced adaptability to new learning challenges. © 2013 Wiley Periodicals, Inc.     

Novel learning accelerates systems consolidation of a contextual fear memory

After initial encoding memories may undergo a time‐dependent reorganization, becoming progressively independent from the hippocampus (HPC) and dependent on cortical regions such as the anterior cingulate cortex (ACC). Although the mechanisms underlying systems consolidation are somewhat known, the factors determining its temporal dynamics are still poorly understood. Here, we studied the influence of novel learning occurring between training and test sessions on the time‐course of HPC‐ and ACC‐dependency of contextual fear conditioning (CFC) memory expression. We found that muscimol was disruptive when infused into the HPC up to 35 days after training, while the ACC is vulnerable only after 45 days. However, when animals were subjected to a series of additional, distinct tasks to be learned within the first 3 weeks, muscimol became effective sooner. Muscimol had no effect in the HPC at 20 days after training, exactly when the ACC becomes responsive to this treatment. Thus, our data indicates that the encoding of new information generates a tight interplay between distinct memories, accelerating the reorganization of previously stored long term memories between the hippocampal and cortical areas. © 2016 Wiley Periodicals, Inc.     

Early signal from the hippocampus for memory encoding

The mediotemporal lobe (MTL), including the hippocampus, is involved in all stages of episodic memory including memory encoding, consolidation, and retrieval. However, the exact timing of the hippocampus' involvement immediately after stimulus encounter remains unclear. In this study, we used high‐density 156‐channel electroencephalography to study the processing of entirely new stimuli, which had to be encoded, in comparison to highly overlearned stimuli. Sixteen healthy subjects performed a continuous recognition task with meaningful pictures repeated up to four consecutive times. Waveform and topographic cluster analyses of event‐related potentials revealed that new items, in comparison to repetitions, were processed significantly differently at 220–300 ms. Source estimation localized activation for processing new stimuli in the right MTL. Our study demonstrates the occurrence of a transient signal from the MTL in response to new information already at 200–300 ms poststimulus onset, which presumably reflects encoding as an initial step toward memory consolidation.     

Intact CA3 in the hippocampus is only sufficient for contextual behavior based on well‐learned and unaltered visual background

Computational models suggest that the dentate gyrus and CA3 subfields of the hippocampus are responsible for discrete memory representations using pattern separation and pattern completion when a modified external stimulus is recognized as an old memory or encoded as a new memory. Experimental evidence of such computational processes in the hippocampus has been obtained mostly from spatial navigational tasks, and little is known about the proposed computational functions of the hippocampal subfields in “nonspatial” memory tasks. We tested whether rats with major damage in the dentate gyrus induced by colchicine lesions could remember patterned visual scene stimuli presented on LCD screens in the background. Rats responded using a touchscreen to indicate the identity of the visual scene. Performance of the lesion group was normal when tested with familiar visual scenes that had been learned prior to surgery. Lesioned rats exhibited severe deficits in learning novel visual scenes, but eventually reached the same level of performance as controls. However, unlike in controls, novel scene‐associated memories formed in the lesion group were unstable and easily disrupted when ambiguous versions of the novel scenes were presented intermixed with the original stimuli. Our findings confirm that the prior computational models can also be applied to the nonspatial memory domain and suggest that the dentate gyrus is not necessary for the retrieval of learned visual scene‐associated behavioral responses but plays a crucial role in forming novel visual scene‐dependent memory and recognizing altered or ambiguous visual scenes in the background. © 2014 Wiley Periodicals, Inc.     

Modification of the responses of hippocampal neurons in the monkey during the learning of a conditional spatial response task

In order to analyze the function of the hippocampus in learning, the activity of single neurons was recorded while monkeys learned a task of the type known to be impaired by damage to the hippocampus. In the conditional response task, the monkey had to learn to make one response when one stimulus was shown, and a different response when a different stimulus was shown. It had previously been shown that there are neurons in the hippocampal formation that respond in this task, to, for example, a combination of a particular visual stimulus that had been associated in previous learning with a particular behavioral response. In the present study, it was found that during such conditional response learning, the activity of 22% of the neurons in the hippocampus and parahippocampal gyrus with activity specifically related to the task altered their responses so that their activity, which was initially equal to the two new stimuli, became progressively differential to the two stimuli when the monkey learned to make different responses to the two stimuli. These changes occurred for different neurons just before, at, or just after the time when the monkey learned the correct response to make to the stimuli. In addition to these neurons, which had differential responses that were sustained for as long as the recordings continued, another population of neurons (45% of those with activity specifically related to the task) developed differential activity to the two new stimuli, yet showed such differential responses transiently for only a small number of trials at about the time when the monkey learned. These findings are consistent with the hypothesis that some synapses on hippocampal neurons modify during this type of learning so that some neurons come to respond to particular stimulus-response associations that are being learned. Further, the finding that many hippocampal neurons started to reflect the new learning, but then stopped responding differentially (the transient neurons), is consistent with the hypothesis that the hippocampal neurons with large sustained changes in their activity inhibited the transient neurons, which then underwent reverse learning, thus providing a competitive mechanism by which not all neurons are allocated to any one learned association or event.     

Exposure to oestrogen prenatally does not interfere with the normal female-typical development of odour preferences

The neural mechanisms controlling mate recognition and heterosexual partner preference are sexually differentiated by perinatal actions of sex steroid hormones. We previously showed that the most important action of oestrogen during prenatal development is to defeminise and, to some extent, masculinise brain and behaviour in mice. Female mice deficient in alpha-foetoprotein (AFP) due to a targeted mutation in the Afp gene (AFP-KO) do not show any female sexual behaviour when paired with an active male because they lack the protective action of AFP against maternal oestrogens. In the present study, we investigated whether odour preferences, another sexually differentiated trait in mice, are also defeminised and/or masculinised in AFP-KO females due to their prenatal exposure to oestrogens. AFP-KO females of two background strains (CD1 and C57Bl/6j) preferred to investigate male over female odours when given the choice between these two odour stimuli in a Y-maze, and thus remained very female-like in this regard. Thus, the absence of lordosis behaviour in these females cannot be explained by a reduced motivation of AFP-KO females to investigate male-derived odours. Furthermore, the presence of a strong male-directed odour preference in AFP-KO females suggests a postnatal contribution of oestrogens to the development of preferences to investigate opposite-sex odours.     

Fornix--thalamus fibers, motivational states, and contextual retrieval.

The effect of selectively transecting fornix fibers bound for the anterior thalamic nuclei upon the means by which motivational states influence selection of learned responses was assessed. Rats were deprived of food or water on alternate days. During short sessions they had an opportunity to learn to turn one direction to obtain food and the opposite direction to obtain water in the same T-maze. The control group was a combination of animals which had received sham operations and those in which the attempted transection was off target. Experimental animals behaved much less differentially than controls. The performance levels of the experimental animals in obtaining food and water were more negatively correlated than those of controls. During early stages of the learning procedure the experimental animals were more likely to develop strong individual response preferences or biases than controls. Experimental animals also required more trials to reach criterion than controls. The results are interpreted as indicating that after transection of connections between the subiculum and the anterior thalamic nuclei, motivational states no longer act conditionally upon the selection of learned behavior for performance. Rather they are pooled together with other stimuli. Such an interpretation is derived from the theory that the hippocampus is part of a system mediating contextual retrieval of information from memory.     

Combined modulating effects of the general arousal and the specific hunger arousal on the olfactory bulb responses in the rat.

The combined modulating effects of the general level of arousal and specific hunger arousal on the olfactory bulb responses were investigated in the rat. Vigilance state parameters and multi-unit mitral cell activity were recorded in freely moving animals stimulated by control odours and by their usual food odour, either in the hungry or the satiated state. The nutritionally modulated bulb responses towards food odour were observed only for high arousal level (wakefulness). In rapid eye movement sleep (REMS), no olfactory response occurred. In slow wave sleep (SWS), one observed either a high bulb responsiveness to stimuli with neocortical arousal, or a general inexcitability. Each odorous stimulus in SWS elicited a higher neocortical arousal rate in the hungry than in the satiated state, as did food odour compared with control odours in both nutritional states. In SWS, a progressive alteration of the nutritionally modulated responses occurred at first at the bulb level and later for inner structures. Rats fed 2 h a day displayed a reversed circadian sleep-waking cycle and a lower SWS proportion compared with rats fed ad libitum. The hunger arousal could quantitatively and qualitatively modulate the activity of structures regulating the sleep-waking pattern.     

Contributions of the hippocampus and entorhinal cortex to rapid visuomotor learning in rhesus monkeys

The hippocampus and adjacent structures in the medial temporal lobe are essential for establishing new associative memories. Despite this knowledge, it is not known whether the hippocampus proper is essential for establishing such memories, nor is it known whether adjacent regions like the entorhinal cortex might contribute. To test the contributions of these regions to the formation of new associative memories, we trained rhesus monkeys to rapidly acquire arbitrary visuomotor associations, i.e., associations between visual stimuli and spatially directed actions. We then assessed the effects of reversible inactivations of either the hippocampus (Experiment 1) or entorhinal cortex (Experiment 2) on the within‐session rate of learning. For comparison, we also evaluated the effects of the inactivations on performance of problems of the same type that had been well learned prior to any inactivations. We found that inactivation of the entorhinal cortex but not hippocampus produced impairments in acquiring novel arbitrary associations. The impairment did not extend to the familiar, previously established associations. These data indicate that the entorhinal cortex is causally involved in establishing new associations, as opposed to retrieving previously learned associations. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.     

Telencephalon and geometric space in goldfish

Neuroanatomical evidence indicates that the lateral pallium (LP) of ray-finned fishes could be homologous to the hippocampus of mammals and birds. Recent studies have found that hippocampus of mammals and birds is critical for learning geometric properties of space. In this work, we studied the effects of lesions to the lateral pallium of goldfish on the encoding of geometric spatial information. Goldfish with telencephalic lesions were trained to search for a goal in a rectangular-shaped arena containing one different wall that served as the only distinctive environmental feature. Although fish with lateral pallium lesions learned the task even faster than sham and medial pallium (MP)-lesioned animals, subsequent probe trials showed that they were insensitive to geometric information. Sham and medial pallium-lesioned animals could use both geometric and feature information to locate the goal. By contrast, fish with lateral palium lesions relied exclusively on the feature information provided by the wall of a different colour. These results indicate that lesions to the lateral pallium of goldfish, like hippocampal lesions in mammals and birds, selectively impair the encoding of geometric spatial information of environmental space. Thus, the forebrain structures of teleost fish that are neuroanatomically equivalent to the mammalian and avian hippocampus also share a central role in supporting spatial cognition. Present results suggest that the presence of a hippocampal-dependent memory system implicated in the processing of geometric spatial information is an ancient feature of the vertebrate forebrain that has been conserved during the divergent evolution of different vertebrate groups.     

Relational learning and transitive expression in aging and amnesia

Aging has been associated with a decline in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm (Bunsey and Eichenbaum (1996) Nature 379:255‐257) , which traditionally has been used in nonhuman animal research, this work examined the extent to which aging is accompanied by deficits in relational learning and flexible expression of relational information. Older adults' performance was additionally contrasted with that of amnesic case DA to understand the critical contributions of the medial temporal lobe, and specifically, the hippocampus, which endures structural and functional changes in healthy aging. Participants were required to select the correct choice item (B versus Y) based on the presented sample item (e.g., A). Pairwise relations must be learned (A‐>B, B‐>C, C‐>D) so that ultimately, the correct relations can be inferred when presented with a novel probe item (A‐>C?Z?). Participants completed four conditions of transitivity that varied in terms of the degree to which the stimuli and the relations among them were known pre‐experimentally. Younger adults, older adults, and DA performed similarly when the condition employed all pre‐experimentally known, semantic, relations. Older adults and DA were less accurate than younger adults when all to‐be‐learned relations were arbitrary. However, accuracy improved for older adults when they could use pre‐experimentally known pairwise relations to express understanding of arbitrary relations as indexed through inference judgments. DA could not learn arbitrary relations nor use existing knowledge to support novel inferences. These results suggest that while aging has often been associated with an emerging decline in hippocampal function, prior knowledge can be used to support novel inferences. However, in case DA, significant damage to the hippocampus likely impaired his ability to learn novel relations, while additional damage to ventromedial prefrontal and anterior temporal regions may have resulted in an inability to use prior knowledge to flexibly express indirect relational knowledge. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.