The hippocampus is required for short-term topographical memory in humans

The hippocampus plays a crucial role within the neural systems for long-term memory, but little if any role in the short-term retention of some types of stimuli. Nonetheless, the hippocampus may be specialized for allocentric topographical processing, which impacts on short-term memory or even perception. To investigate this we developed performance-matched tests of perception (match-to-sample) and short-term memory (2 s delayed-match-to-sample) for the topography and for the nonspatial aspects of visual scenes. Four patients with focal hippocampal damage and one with more extensive damage, including right parahippocampal gyrus, were tested. All five patients showed impaired topographical memory and spared nonspatial processing in both memory and perception. Topographical perception was profoundly impaired in the patient with parahippocampal damage, mildly impaired in two of the hippocampal cases, and clearly preserved in the other two hippocampal cases (including one with dense amnesia). Our results suggest that the hippocampus supports allocentric topographical processing that is indispensable when appropriately tested after even very short delays, while the presence of the sample scene can allow successful topographical perception without it, possibly via a less flexible parahippocampal representation.     

Equivalent impairment of spatial and nonspatial memory following damage to the human hippocampus.

The hippocampus has sometimes been proposed to function as a cognitive map, a memory system that stores information about allocentric space. Work with experimental animals and memory-impaired patients has raised difficulties with this view by showing that the hippocampus is not performing an exclusively spatial function. However, the possibility has remained that the hippocampus plays a special role in spatial memory or a disproportionately large role in spatial memory compared to other kinds of memory. This study compared spatial and nonspatial memory in amnesic patients with lesions of the hippocampal formation or diencephalon. Subjects studied an array of 16 toy objects and were subsequently tested for object recall, object recognition, and memory for the location of the objects. Control subjects were tested after long retention intervals in order to equate their object memory performance with that of the patients. The main finding was that, when the performance of amnesic patients on the object memory tests was matched to the object memory performance of control subjects, spatial memory performance of the amnesic patients also matched the spatial memory performance of the control subjects. The results were the same for the two groups of patients. These findings suggest that the hippocampus is not especially involved in spatial memory. Spatial memory is simply one instance of a broader category of memory that requires the hippocampus. While cognitive mapping in its most abstract sense may describe hippocampal function, our results support alternative formulation, suggesting that the hippocampus is necessary for the rapid acquisition of relational, configural, or declarative (as opposed to purely spatial) information.     

The extended hippocampal-diencephalic memory system: enriched housing promotes recovery of the flexible use of spatial representations after anterior thalamic lesions

The anterior thalamic (AT) nuclei constitute an important component of an extended hippocampal-diencephalic system, and severe persisting memory deficits are normally found after AT damage. This study examined whether postoperative enrichment promotes the recovery of the flexible use of spatial representations in rats with AT lesions. After training to swim from a single constant start position to a submerged platform in a Morris water maze, rats with AT lesions that were housed in standard cages (AT-Std) performed poorly when required to swim to the platform from novel start positions during probe trials. By contrast, rats with AT lesions but housed in enriched environments (AT-Enr), like sham-lesion rats, showed relatively little disruption when tested with novel start positions. AT-Std rats also initially showed impaired acquisition of the task, whereas AT-Enr rats learned at a similar rate to that of the Sham-Std group. Beneficial effects of enrichment were replicated in the subsequent standard water maze procedure that used varying start positions throughout training to acquire a new platform location. Although it is clear that AT damage can severely disrupt episodic-like memory processes, and appear to be a core part of the interlinked neural systems subserving episodic memory, the current findings strongly encourage study on the adaptive response of the brain to thalamic lesions and prospects for the development of rehabilitation programs in cases of anterograde amnesia associated with diencephalic injury.     

Muscarinic receptor blockade in ventral hippocampus and prelimbic cortex impairs memory for socially transmitted food preference

Acetylcholine is involved in learning and memory and, particularly, in olfactory tasks, but reports on its specific role in consolidation processes are somewhat controversial. The present experiment sought to determine the effects of blocking muscarinic cholinergic receptors in the ventral hippocampus (vHPC) and the prelimbic cortex (PLC) on the consolidation of social transmission of food preference, an odor‐guided relational task that depends on such brain areas. Adult male Wistar rats were bilaterally infused with scopolamine (20 μg/site) immediately after social training and showed impairment, relative to vehicle‐injected controls, in the expression of the task measured 24 h after learning. Results indicated that scopolamine in the PLC completely abolished memory, suggesting that muscarinic transmission in this cortical region is crucial for consolidation of recent socially acquired information. Muscarinic receptors in the vHPC contribute in some way to task consolidation, as the rats injected with scopolamine in the vHPC showed significantly lower trained food preference than control rats, but higher than both chance level and that of the PLC‐injected rats. Behavioral measures such as social interaction, motivation to eat, neophobia, or exploration did not differ between rats infused with scopolamine or vehicle. Such data suggest a possible differential role of muscarinic receptors in the PLC and the vHPC in the initial consolidation of a naturalistic form of nonspatial relational memory. © 2008 Wiley‐Liss, Inc.     

Functional cross‐hemispheric shift between object‐place paired associate memory and spatial memory in the human hippocampus

The hippocampus plays critical roles in both object‐based event memory and spatial navigation, but it is largely unknown whether the left and right hippocampi play functionally equivalent roles in these cognitive domains. To examine the hemispheric symmetry of human hippocampal functions, we used an fMRI scanner to measure BOLD activity while subjects performed tasks requiring both object‐based event memory and spatial navigation in a virtual environment. Specifically, the subjects were required to form object‐place paired associate memory after visiting four buildings containing discrete objects in a virtual plus maze. The four buildings were visually identical, and the subjects used distal visual cues (i.e., scenes) to differentiate the buildings. During testing, the subjects were required to identify one of the buildings when cued with a previously associated object, and when shifted to a random place, the subject was expected to navigate to the previously chosen building. We observed that the BOLD activity foci changed from the left hippocampus to the right hippocampus as task demand changed from identifying a previously seen object (object‐cueing period) to searching for its paired‐associate place (object‐cued place recognition period). Furthermore, the efficient retrieval of object‐place paired associate memory (object‐cued place recognition period) was correlated with the BOLD response of the left hippocampus, whereas the efficient retrieval of relatively pure spatial memory (spatial memory period) was correlated with the right hippocampal BOLD response. These findings suggest that the left and right hippocampi in humans might process qualitatively different information for remembering episodic events in space. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Deficits in egocentric-updating and spatial context memory in a case of developmental amnesia

Patients with developmental amnesia usually suffer from both episodic and spatial memory deficits. DM, a developmental amnesic, was impaired in her ability to process self-motion (i.e., idiothetic) information while her ability to process external stable landmarks (i.e., allothetic) was preserved when no self-motion processing was required. On a naturalistic and incidental episodic task, DM was severely and predictably impaired on both free and cued recall tasks. Interestingly, when cued, she was more impaired at recalling spatial context than factual or temporal information. Theoretical implications of that co-occurrence of deficits and those dissociations are discussed and testable cerebral hypothesis are proposed.     

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.     

Place-related neural responses in the monkey hippocampal formation in a virtual space

Place cells in the rodent hippocampal formation (HF) are suggested to be the neural substrate for a spatial cognitive map. This specific spatial property of the place cells are regulated by both allothetic cues (i.e., intramaze local and distal cues) as well as idiothetic sensory inputs; the context signaled by the distal cues allows local and idiothetic cues to be employed for spatial tuning within the maze. To investigate the effects of distal cues on place-related activity of primate HF neurons, 228 neurons were recorded from the monkey HF during virtual navigation in a similar situation to a rodent water maze, in which distal cues were important to locate the animal's position. A subset of 72 neurons displayed place-related activity in one or more virtual spaces. Most place-related responses disappeared or changed their spatial tuning (i.e., remapping) when the arrangements of the distal cues were altered/moved in the virtual spaces. These specific features of the monkey HF might underlie neurophysiological bases of human episodic memory.     

Effects of chronic alcohol consumption or Diazepam administration on item recognition and temporal ordering in a spatial working memory task in mice

This study was aimed at determining the effects of either Diazepam administration or chronic alcohol consumption (CAC) on spatial memory measured by concurrent discriminations in an eight arm radial maze using mice as subjects. Two different protocols involving a non-matching rule were used to evaluate either temporal order (recurrent items) or item recognition (non-recurrent items). Results showed that both Diazepam administration and CAC produced a memory deficit which was primarily observed in the temporal task, whereas item recognition was spared. These data show that Diazepam and CAC produced similar memory impairments. Thus, our study stressed the potential importance of the GABA/BDZ dysfunction in the production of organic amnesia of alcoholic origin. The overall analysis of the data suggests that both CAC and Diazepam injections would impair forms of memory sustained by automatic or incidental learning.     

Retrograde amnesia in rats with lesions to the hippocampus on a test of spatial memory

The present study examined remote spatial memory in a test that spans several months to determine whether remote memories are spared relative to more recent ones, as predicted by models of memory consolidation. At 3, 6 or 12 months of age, groups of rats received forced-choice training as to the location of food reward in a cross maze. At 12.5 months, rats received bilateral neurotoxic lesions to the hippocampus or a control surgical procedure and 2 weeks later their memory for the spatial location was tested. Their performance was compared to that of rats with hippocampal or control lesions with no prior training on several measures of savings. The hippocampal group with no pre-training, as expected, was severely impaired in learning the location of the food reward. Compared to this group, rats with hippocampal lesions that were pre-trained consistently performed better at the shortest training-surgery interval but not at the longer ones. That is, rats with hippocampal lesions exhibited retrograde amnesia at all training-surgery intervals and a forgetting curve that paralleled that of the control groups. The results were interpreted within a framework that distinguishes between relational and associative context, and as providing evidence that the hippocampus is necessary for the retention and retrieval of memories that are bound to relational context, regardless of the age of the memory.     

Bilateral hippocampal pathology impairs topographical and episodic memory but not visual pattern matching.

A virtual reality environment was used to test memory performance for simulated "real-world" spatial and episodic information in a 22-year-old male, Jon, who has selective bilateral hippocampal pathology caused by perinatal anoxia. He was allowed to explore a large-scale virtual reality town and was then tested on his memory for spatial layout and for episodes experienced. Topographical memory was tested by assessing his ability to navigate, recognize previously visited locations, and draw maps of the town. Episodic memory was assessed by testing the retrieval of simulated events which consisted of collecting objects from characters while following a route through the virtual town. Memory for the identity of objects, as well as for where they were collected, from whom, and in what order, was also tested. While the first task tapped simple recognition memory, the latter three tested memory for context. Jon was impaired on all topographical tasks and on his recall of the context-dependent questions. However, his recognition of objects from the virtual town, and of "topographical" scenes (as evaluated by standard neuropsychological tests), was not impaired. These findings are consistent with the view that the hippocampus is involved in navigation, recall of long term allocentric spatial information and context-dependent episodic memory, but not visual pattern matching.     

The hippocampus, time and working memory

Rats were trained on a discrete trial working memory leverpress alternation task, following hippocampal lesions (HC), cortical control lesions (CC) or sham operations (SO). Each trial consisted of a forced information response, for which a randomly selected lever was presented followed by a free choice stage, when both levers were presented. The rats were rewarded for pressing the lever which had not been presented at the information stage. When the information response was not rewarded, all rats learnt the task equally well at IRIs of up to 12.75 sec. When the information response was rewarded, the HC rats showed impaired choice accuracy. The extent of this impairment depended on the IRI, being greatest at long IRIs, and least at short ones. Varying the number of leverpresses required to complete the information response affected choice accuracy equivalently in all groups: all rats chose significantly less accurately when only one leverpress was required than when ten leverpresses were required. There was no interaction between the lesion treatments and the information response requirements. It was concluded that both the length of the IRI and the occurrence of events during the IRI determine the extent of the hippocampal lesion-induced performance deficit in working memory tasks. It is proposed that hippocampal damage disrupts an intermediate-term, high-capacity memory buffer, but leaves both a residual short-term memory system and the long-term retention of associations unaffected. This proposal leads to the prediction that reference memory tasks should also be affected by hippocampal lesions when a delay is introduced between making a response and being rewarded for doing so.     

Sleep to find your way: the role of sleep in the consolidation of memory for navigation in humans

Although a large body of evidence indicates that sleep plays an important role in learning and memory processes, the actual existence of a sleep-dependent spatial memory consolidation has been not firmly established. Here, by using a computerized 3D virtual navigation tool, we were able to show that topographical orientation in humans largely benefits from sleep after learning, while 10 h of wakefulness during the daytime do not exert similar beneficial effects. In particular, navigation performance enhancement needs sleep in the first post-training night, and no further improvements were seen after a second night of sleep. On the other hand, sleep deprivation hinders any performance enhancement and exerts a proactive disruption of spatial memory consolidation, since recovery sleep do not revert its effects. Spatial memory performance does not benefit from the simple passage of time, and a period of wakefulness between learning and sleep does not seem to have the role of stabilizing memory traces. In conclusion, our results indicate that spatial performance improvement is observed only when learning is followed by a period of sleep, regardless of the retention interval length.     

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval,and combining them attenuates the acquisition rate of spatial reference memory

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over‐generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.     

Navigation expertise and the human hippocampus: a structural brain imaging analysis

Grey matter volume in the posterior hippocampus of London taxi drivers is greater than in age-matched controls, and the size of this increase correlates positively with time spent taxi driving (E.A. Maguire et al., 2000. Proc Natl Acad Sci USA 97: 4398-4403). This change suggests that increased posterior hippocampal grey matter volume is acquired in response to increased taxi driving experience, perhaps reflecting their detailed representation of the city. However, an alternate hypothesis is that the difference in hippocampal volume is instead associated with innate navigational expertise, leading to an increased likelihood of becoming a taxi driver. To investigate this possibility, we used structural brain imaging and voxel-based morphometry (VBM) to examine a group of subjects who were not taxi drivers. Despite this group showing a wide range of navigational expertise, there was no association between expertise and posterior hippocampal grey matter volume (or, indeed, grey matter volume throughout the brain). This failure to find an association between hippocampal volume and navigational expertise thus suggests that structural differences in the human hippocampus reflect the detail and/or duration of use of the spatial representation acquired, and not innate navigational expertise per se.     

Environmental deformations dynamically shift human spatial memory

Place and grid cells in the hippocampal formation are commonly thought to support a unified and coherent cognitive map of space. This mapping mechanism faces a challenge when a navigator is placed in a familiar environment that has been deformed from its original shape. Under such circumstances, many transformations could plausibly serve to map a navigator's familiar cognitive map to the deformed space. Previous empirical results indicate that the firing fields of rodent place and grid cells stretch or compress in a manner that approximately matches the environmental deformation, and human spatial memory exhibits similar distortions. These effects have been interpreted as evidence that reshaping a familiar environment elicits an analogously reshaped cognitive map. However, recent work has suggested an alternative explanation, whereby deformation‐induced distortions of the grid code are attributable to a mechanism that dynamically anchors grid fields to the most recently experienced boundary, thus causing history‐dependent shifts in grid phase. This interpretation raises the possibility that human spatial memory will exhibit similar history‐dependent dynamics. To test this prediction, we taught participants the locations of objects in a virtual environment and then probed their memory for these locations in deformed versions of this environment. Across three experiments with variable access to visual and vestibular cues, we observed the predicted pattern, whereby the remembered locations of objects were shifted from trial to trial depending on the boundary of origin of the participant's movement trajectory. These results provide evidence for a dynamic anchoring mechanism that governs both neuronal firing and spatial memory.     

Computational analysis of the role of the hippocampus in memory

The authors draw together the results of a series of detailed computational studies and show how they are contributing to the development of a theory of hippocampal function. A new part of the theory introduced here is a quantitative analysis of how backprojections from the hippocampus to the neocortex could lead to the recall of recent memories. The theory is then compared with other theories of hippocampal function. First, what is computed by the hippocampus is considered. The hypothesis the authors advocate, on the basis of the effects of damage to the hippocampus and neuronal activity recorded in it, is that it is involved in the formation of new memories by acting as an intermediate-term buffer store for information about episodes, particularly for spatial, but probably also for some nonspatial, information. The authors analyze how the hippocampus could perform this function, by producing a computational theory of how it operates, based on neuroanatomical and neurophysiological information about the different neuronal systems contained within the hippocampus. Key hypotheses are that the CA3 pyramidal cells operate as a single autoassociation network to store new episodic information as it arrives via a number of specialized preprocessing stages from many association areas of the cerebral cortex, and that the dentate granule cell/mossy fiber system is important, particularly during learning, to help to produce a new pattern of firing in the CA3 cells for each episode. The computational analysis shows how many memories could be stored in the hippocampus and how quickly the CA3 autoassociation system would operate during recall. The analysis is then extended to show how the CA3 system could be used to recall a whole episodic memory when only a fragment of it is presented. It is shown how this recall could operate using modified synapses in backprojection pathways from the hippocampus to the cerebral neocortex, resulting in reinstatement of neuronal activity in association areas of the cerebral neocortex similar to that present during the original episode. The recalled information in the cerebral neocortex could then be used by the neocortex in the formation of long-term memories. © 1994 Wiley-Liss, Inc.     

Dissociable anterograde amnesic effects of retrosplenial cortex and hippocampal lesions on spontaneous object recognition memory in rats

The amnesic effects of excitotoxic lesions of the rat retrosplenial cortex (RS) and hippocampus (HPC) in the spontaneous object recognition (SOR) performance were investigated. The SOR test consisted of the sample‐exposure session(s) and a test session. First, to test retrograde amnesia, rats received four sample‐exposure sessions within a day at 4 weeks and 1 day before the surgery, respectively. In the test sessions conducted 1 week after the surgery, both lesion groups showed a temporally ungraded retrograde amnesia. Second, to test anterograde amnesia, 1‐ and 4‐week retention intervals were inserted between the four sample‐exposure sessions and the test session. The RS‐lesioned rats showed a retention interval‐dependent impairment in the test sessions, while the HPC‐lesioned rats showed an impairment regardless of the retention interval. Finally, to test short‐term recognition memory, 5‐ or 30‐min delay was interposed between the single sample‐exposure session and the test session. Both lesion groups performed normally irrespective of the delay length. These results suggest that both the RS and HPC are important for long‐term object recognition memory, but these areas have different roles in it. © 2012 Wiley Periodicals, Inc.     

Severe tactual memory deficits in monkeys after combined removal of the amygdala and hippocampus

Monkeys with bilateral removals of both the amygdaloid complex and hippocampal formation were far more severely impaired on a tactual memory task than were monkeys with removal of either structure alone. These data parallel earlier findings on visual memory in monkeys and suggest that: (i) the memory deficit following combined ablations of the amygdala and hippocampus is multimodal; and (ii) the global anterograde amnesia observed in patients with medial temporal-lobe damage is also due to combined damage to these two structures.