Showing papers in "Hippocampus in 1999"

Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval.

Abstract: Early neuroimaging studies often failed to obtain evidence of medial temporal lobe (MTL) activation during episodic encoding or retrieval, but a growing number of studies using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have provided such evidence. We review data from fMRI studies that converge on the conclusion that posterior MTL is associated with episodic encoding; too few fMRI studies of retrieval have reported MTL activations to allow firm conclusions about their exact locations. We then turn to a recent meta-analysis of PET studies (Lepage et al., Hippocampus 1998;8:313- 322) that appears to contradict the fMRI encoding data. Based on their analysis of the rostrocaudal distribution of activations reported during episodic encoding or retrieval, Lepage et al. (1998) concluded that anterior MTL is strongly associated with episodic encoding, whereas posterior MTL is strongly associated with episodic retrieval. After consider- ing the evidence reviewed by Lepage et al. (1998) along with additional studies, we conclude that PET studies of encoding reveal both anterior and posterior MTL activations. These observations indicate that the contradic- tion between fMRI and PET studies of encoding was more apparent than real. However, PET studies have reported anterior MTL encoding activa- tions more frequently than have fMRI studies. We consider possible sources of these differences. Hippocampus 1999;9:7-24. r 1999 Wiley-Liss, Inc.

High-frequency oscillations in human brain.

Abstract: Ripples are 100–200 Hz short-duration oscillatory field potentials that have recently been recorded in rat hippocampus and entorhinal cortex. They reflect fast IPSPs on the soma of pyramidal cells, which occur during synchronous afferent excitation of principal cells and interneuron networks. We now describe two similar types of high-frequency field oscillations recorded from the entorhinal cortex and hippocampus of patients with mesial temporal lobe epilepsy. The first type appears be the human equivalent of normal ripples in the rat. The second, which we have termed fast ripples (FR), are in the frequency range of 250–500 Hz. FR are found in the epileptogenic region and may reflect pathological hypersynchronous population spikes of bursting pyramidal cells. Hippocampus 1999;9:137–142. © 1999 Wiley-Liss, Inc.

Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5.

Abstract: We investigated the role of NMDA receptors in memory encoding and retrieval. A delayed matching-to-place (DMP) paradigm in the watermaze was used to examine 1-trial spatial memory in rats. Over periods of up to 21 days, 4 daily trials were given to an escape platform hidden in a new location each day, with the memory interval (ITI) varying from 15 sec to 2 hours between trials 1 and 2, but always at 15 sec for the remaining ITIs. Using chronic i.c.v. infusions of D-AP5, acute intrahippocampal infusions, ibotenate hippocampus + dentate lesions and relevant aCSF or sham surgery control groups, we established: (1) the DMP task is hippocampal-dependent; (2) D-AP5 causes a delay-dependent impairment of memory in which the Groups x Delay interaction was significant on two separate measures of performance; (3) this memory impairment also occurs with acute intrahippocampal infusions; (4) the impairment occurs irrespective of whether the animals stay in or are removed from the training context during the memory delay interval; and (5) D-AP5 affects neither the retrieval of information about the spatial layout of the environment, nor memory of where the escape platform had been located on the last day before the start of chronic D-AP5 infusion. LTP in vivo in the dentate gyrus was blocked in the chronically-infused D-AP5 rats and HPLC measurements at sacrifice revealed appropriate intrahippocampal levels. Acute intrahippocampal infusion of radiolabelled D-AP5 revealed relatively restricted diffusion and was used to estimate whole-tissue hippocampal drug concentrations. These results indicate that (1) short-term memory for spatial information is independent of NMDA receptors; (2) the rapid consolidation of spatial information into long-term memory requires activation of hippocampal NMDA receptors; (3) NMDA receptors are not involved in memory retrieval; and (4) the delay-related effects of NMDA receptor antagonists on performance of this task cannot be explained in terms of sensorimotor disturbances. The findings relate to the idea that hippocampal synaptic plasticity is involved in event-memory (Morris and Frey, Phil Trans R Soc Lond B 1997;352:1489–1503) and to a computational model of one-trial DMP performance of Foster et al. (unpublished data). Hippocampus 9:118–136, 1999. © 1999 Wiley-Liss, Inc.

Hippocampectomy disrupts auditory trace fear conditioning and contextual fear conditioning in the rat.

Abstract: The hippocampus is believed to be an important structure for learning tasks that require temporal processing of information. The trace classical conditioning paradigm requires temporal processing because the conditioned stimulus (CS) and the unconditioned stimulus (US) are temporally separated by an empty trace interval. The present study sought to determine whether the hippocampus was necessary for rats to perform a classical trace fear conditioning task in which each of 10 trials consisted of an auditory tone CS (15-s duration) followed by an empty 30-s trace interval and then a fear-producing floor-shock US (0.5-s duration). Several weeks prior to training, animals were anesthetized and given aspiration lesions of the neocortex (NEO; n = 6), hippocampus and overlying neocortex (HIPP; n = 7), or no lesions at all (control; n = 6). Approximately 24 h after trace conditioning, NEO and control animals showed a significant decrease in movement to a CS-alone presentation that was indicative of a conditioned fear response. Animals in the HIPP group did not show conditioned fear responses to the CS alone, nor did a pseudoconditioning group (n = 7) that was trained with unpaired CSs and USs. Furthermore, all groups except the HIPP group showed conditioned fear responses to the original context in which they received shock USs. One week later, HIPP, NEO, and control animals received delay fear-conditioning trials with no trace interval separating the CS and US. Six of seven HIPP animals could perform the delay version, but none could perform the trace version. This result suggests that the trace fear task is a reliable and useful model for examining the neural mechanisms of hippocampally dependent learning. Hippocampus 1998;8:638–646. © 1998 Wiley-Liss, Inc.

Exposing rats to a predator impairs spatial working memory in the radial arm water maze

Abstract: This series of studies investigated the effects of predator exposure on working memory in rats trained on the radial arm water maze (RAWM). The RAWM is a modified Morris water maze that contains four or six swim paths (arms) radiating out of an open central area, with a hidden platform located at the end of one of the arms. The hidden platform was located in the same arm on each trial within a day and was in a different arm across days. Each day rats learned the location of the hidden platform during acquisition trials, and then the rats were removed from the maze for a 30-min delay period. During the delay period, the rats were placed either in their home cage (nonstress condition) or in close proximity to a cat (stress condition). At the end of the delay period, the rats were run on a retention trial, which tested their ability to remember which arm contained the platform that day. The first experiment confirmed that the RAWM is a hippocampal-dependent task. Rats with hippocampal damage were impaired at learning the location of the hidden platform in the easiest RAWM under control (non-stress) conditions. The next three experiments showed that stress had no effect on memory in the easiest RAWM, but stress did impair memory in more difficult versions of the RAWM. These findings indicate that the capacity for stress to impair memory is influenced not only by the brain memory system involved in solving the task (hippocampal versus nonhippocampal), but also by the difficulty of the task. This work should help to resolve some of the confusion in the literature regarding the heterogeneous effects of stress on hippocampal-dependent learning and memory.

Hippocampal system and declarative (relational) memory: Summarizing the data from functional neuroimaging studies

Abstract: In the last several years there have been impressive strides in the ability to explore the nature of hippocampal system functioning in humans by employing functional neuroimaging methods, permitting such methods to be used in conjunction with neuropsychological methods to better understand the role of the hippocampal system in memory. In this paper, we review the literature on functional imaging studies of the hippocampal system, summarizing the data and testing these data against a number of theories or explanatory accounts of hippocampal function. We consider five alternative explanatory accounts of, or ideas about, hippocampal function- some from already existing work, for which the functional imaging data can provide a new test, and others that have emerged directly from the functional imaging work, and that have yet to be tested for their fit of data from neuropsychological methods. We conclude that the relational (declarative) memory account, in which it is proposed that the hippocampal system plays a critical role in binding together multiple inputs to permit representations of the relations among the constituent elements of scenes or events, can better accommodate the full range of imaging (and other existing) data than any other explanatory account of hippocampal function.

Differential modulation of a common memory retrieval network revealed by positron emission tomography.

Abstract: Functional neuroimaging is uniquely placed to examine the dynamic nature of normal human memory, the distributed brain networks that support it, and how they are modulated. Memory has traditionally been classified into context-specific memories personally experienced (“episodic memory”) and impersonal non–context-specific memories (“semantic memory”). However, we suggest that another useful distinction is whether events are personally relevant or not. Typically the factors of personal relevance and temporal context are confounded, and it is as yet not clear the precise influence of either on how memories are stored or retrieved. Here we focus on the retrieval of real-world memories unconfounding personal relevance and temporal context during positron emission tomography (PET) scanning. Memories differed along two dimensions: They were personally relevant (or not) and had temporal specificity (or not). Recollection of each of the resultant four memory subtypes—autobiographical events, public events, autobiographical facts, and general knowledge—was associated with activation of a common network of brain regions. Within this system, however, enhanced activity was observed for retrieval of personally relevant, time-specific memories in left hippocampus, medial prefrontal cortex, and left temporal pole. Bilateral temporoparietal junctions were activated preferentially for personal memories, regardless of time specificity. Finally, left parahippocampal gyrus, left anterolateral temporal cortex, and posterior cingulate cortex were involved in memory retrieval irrespective of person or time. Our findings suggest that specializations in memory retrieval result from associations between subsets of regions within a common network. We believe that these findings throw new light on an old debate surrounding episodic and declarative theories of memory and the precise involvement of the hippocampus. Hippocampus 1999;9:54–61. © 1999 Wiley-Liss, Inc.

Spatial view cells and the representation of place in the primate hippocampus.

Abstract: The information represented in the primate hippocampus is being analysed by making recordings in monkeys actively walking in the laboratory. In a sample of 352 cells recorded in this situation, no "place" cells have so far been found. Instead, we have found a considerable population of "spatial view" cells tuned to respond when the monkey looks at small parts of the environment. We have been able to demonstrate (1) that these hippocampal neurons respond to a view of space "out there," not to the place where the monkey is; (2) that the responses depend on where the monkey is looking, by measuring eye position; (3) that the responses in some cases (e.g., CA1 but not CA3) still occur if the view details are obscured with curtains; (4) that the cells (in, e.g., CA1) retain part of their "space" tuning even in complete darkness, for several minutes; and (5) that the spatial representation is allocentric. The spatial representation is, thus, different from that in the rat hippocampus, in which place cells respond based on where the rat is located. The representation is also different from that described in the parietal cortex, where neurons respond in egocentric coordinates. This representation of space "out there" provided by primate spatial view cells would be an appropriate part of a memory system involved in memories of particular events or episodes, for example, of where in an environment an object was seen. Spatial view cells (in conjunction with whole body motion cells in the primate hippocampus, and head direction cells in the primate presubiculum) would also be useful as part of a spatial navigation system, for which they would provide a memory component.

Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal.

Abstract: Exposure to an enriched environment has been shown to cause an increase in neurogenesis in the dentate gyrus of adult mice. In this study we examined how this experience-dependent response in adult hippocampal neurogenesis of C57BL/6 mice is modulated under the conditions of long-term stimulation and of withdrawal from the enriched environment. We found that a group which experienced withdrawal from the enriched environment 3 months earlier, had more than twice as many proliferating cells in the subgranular zone as controls and mice experiencing long-term stimulation. We propose that the greater number of proliferating cells after withdrawal reflects a survival-promoting effect on the dividing neuronal stem and progenitor cells during the earlier period of stimulation. No differences between the groups were observed in the number of surviving progeny or their phenotypes. Therefore, the existence of more dividing cells in the withdrawal group did not translate into a significant net increase in neurogenesis in the absence of continued stimulation. Similarly, the finding in the group experiencing long-term stimulation showing no clear benefit over controls could be interpreted as a diminished efficiency of continued environmental stimuli to elicit a neurogenic response. Thus, we propose as a working hypothesis that: 1) stimulation early in life may preserve the neurogenic potential in the dentate gyrus, and 2) the novelty of complex stimuli rather than simply continued exposure to complex stimuli elicits the environmental effects on adult hippocampal neurogenesis.

Hippocampus as a memory map: synaptic plasticity and memory encoding by hippocampal neurons.

Abstract: Hippocampal cells contribute to memory by rapidly encoding information about the perceptual and behavioral structure of experience. This paper describes two complementary experimental approaches that illustrate two important mechanisms that confer these properties to hippocampal cells: (1) Enduring spatial memory and stable place fields each depend upon synaptic plasticity mechanisms that normally rely on the same NMDA-receptor mediated metabolic events as long-term potentiation (LTP). Thus, hippocampal cells "learn" to encode information about the perceptual and behavioral structure of experiences. (2) Hippocampal cells encode the structure of experience and respond in a manner inconsistent with a spatial representation. Place fields are distributed heterogeneously in space, their locations are determined by non-geometric information, the population of active cells can indicate more than one location in space, and hippocampal cells encode discriminative stimuli independent of their spatial location. To the extent that the hippocampus encodes a map, it is more simply described as a memory map than a spatial map. Rather than computing spatial locations, the space it encodes is better described as a life or a problem space that encodes the history of experience into the relational structure of episodes.

Do hippocampal pyramidal cells signal non-spatial as well as spatial information?

Abstract: It is generally agreed that the rat hippocampus is involved in spatial memory. Whether this is its sole or primary function, or merely one component of a broader function, is still debated. It has been suggested, for example, that the hippocampus stores information about flexible relations between stimuli, both spatial and non-spatial. In this paper, I reiterate the basic tenet of the cognitive map theory that the processing and storage of spatial information is the primary and perhaps the exclusive role of the hippocampus in the rat, and that data that appear to contradict this have been misinterpreted. These data are found in reports of non-spatial correlates of unit activity recorded in the awake animals and reports of deficits on non-spatial tasks following hippocampal lesions. In this paper, I examine both claims and suggest alternative explanations of the data. The first part of the paper contains a review of some of the properties of hippocampal place cells, which might be misinterpreted as non-spatial in "non-spatial" tasks. For example, if an animal is trained to carry out a sequence of stereotyped actions in different parts of an environment, there will be a strong correlation between the performance of each behaviour and the animal's location, and it is necessary to rule out the locational correlate as the cause of the firing pattern. The second part of the paper looks at the results of experiments on conditioning and non-spatial discrimination tasks and concludes that the results are less supportive of a more general relational theory of hippocampal function than has been suggested. Furthermore, there is often a discrepancy between the correlates of unit firing in non-spatial tasks and the absence of an effect of hippocampal damage on these same or similar tasks. It is concluded that, contrary to the claims of its detractors, the cognitive map theory is still the theory of hippocampal function that is most clearly specified, makes the most testable predictions, and for which there is the strongest experimental support.

Hippocampal formation lesions produce memory impairment in the rhesus monkey.

Abstract: There is much debate over the role of temporal lobe structures in the ability to learn and retain new information. To further assess the contributions of the hippocampal formation (HF), five rhesus monkeys received stereotactically placed ibotenic acid lesions of this region without involvement of surrounding ventromedial temporal cortices. After surgery, the animals were trained on two recognition memory tasks: the Delayed Non-Match to Sample (DNMS) task, which tests the ability to remember specific trial unique stimuli, and the Delayed Recognition Span Task (DRST), which tests the ability to remember an increasing array of stimuli. Relative to normal control monkeys, those with HF lesions demonstrated significant impairments in both learning and memory stages of the DNMS task. Additionally, the HF group was significantly impaired on spatial, color, and object versions of the DRST. Contrary to suggestions that damage to the entorhinal and parahippocampal cortices is required to produce significant behavioral deficits in the monkey, these results demonstrate that selective damage to the HF is sufficient to produce impairments on tasks involving delayed recognition and memory load. This finding illustrates the importance of the HF in the acquisition and retention of new information.

Head direction cells in the primate pre-subiculum.

Abstract: The function of the primate hippocampus and related structures was analysed by making recordings from the hippocampus, subiculum, presubiculum, and parahippocampal gyrus in monkeys actively walking in the laboratory. Head direction cells were found in the presubiculum. The firing rate of these cells was a function of the head direction of the monkey, with a response that was typically 10–100 times larger to the best as compared to the opposite direction. The mean half-amplitude width of the tuning of the cells was 76°. The response of head direction cells in the presubiculum was not influenced by the place where the monkey was, there being the same tuning to head direction at different places in a room, and even outside the room. The response of these cells was also independent of the “spatial view” observed by the monkey, and also the position of the eyes in the head. The average information about head direction was 0.64 bits, about place was 0.10 bits, about spatial view was 0.27 bits, and about eye position was 0.04 bits. The cells maintained their tuning for periods of at least several minutes when the view details were obscured or the room was darkened. This representation of head direction could be useful together with the hippocampal spatial view cells and whole body motion cells found in primates in such spatial and memory functions as path integration. Hippocampus 1999; 9:206–219. © 1999 Wiley-Liss, Inc.

Dentate gyrus-selective colchicine lesion and disruption of performance in spatial tasks: difficulties in "place strategy" because of a lack of flexibility in the use of environmental cues?

Abstract: The effects of intradentate colchicine injections on the performance of tasks requiring spatial working and reference memory are controversial. Multiple-site colchicine injections (7 microg/microl; via a drawn micropipette) throughout the dentate gyrus (DG) of rats (nine sites in each hemisphere, 0.06 microl at each site) selectively destroy about 90% of the DG granule cells, as revealed by quantitative stereological estimates; stereology also revealed minor neuronal losses in the CA4 (33%) and CA1 (23%) subfields, but lack of damage to the CA3 hippocampal subfield. Spatial reference and working memory were assessed in Morris' water maze; in the reference memory task, the rats were required to learn a single, fixed location for the platform over several days of training; in the working memory task, animals were required to learn a new platform location every day, in a matching-to-place procedure. Compared to sham-operated controls, lesioned rats showed significant disruption in acquisition of the reference memory water maze task; however, the data reveal that these rats did acquire relevant information about the task, probably based on guidance and orientation strategies. In a subsequent probe test, with the platform removed, lesioned rats showed disruption in precise indexes of spatial memory (e.g., driving search towards the surroundings of the former platform location), but not in less precise indexes of spatial location. Finally, the lesioned rats showed no improvement in the match-to-place procedure, suggesting that their working memory for places was disrupted. Thus, although capable of acquiring relevant information about the task, possibly through guidance and/or orientation strategies, DG-lesioned rats exhibit a marked difficulty in place strategies. This is particularly evident when these rats are required to deal with one-trial place learning in a familiar environment, such as in the working memory version of the water maze task, which requires flexibility in the use of previously acquired information.

Attractor neural network models of spatial maps in hippocampus.

Abstract: Hippocampal pyramidal neurons in rats are selectively activated at specific locations in an environment (O'Keefe and Dostrovsky, Brain Res 1971;34:171–175). Different cells are active in different places, therefore providing a faithful representation of the environment in which every spatial location is mapped to a particular population state of activity of place cells (Wilson and McNaughton, Science 1993;261:1055–1058; Zhang et al., J Neurosci 1998;79:1017–1044). We describe a theory of the hippocampus, according to which the map results from the cooperative dynamics of network, in which the strength of synaptic interaction between the neurons depends on the distance between their place fields. This synaptic structure guarantees that the network possesses a quasi-continuous set of stable states (attractors) that are localized in the space of neuronal variables reflecting their synaptic interactions, rather than their physical location in the hippocampus. As a consequence of the stable states, the network can exhibit place selective activity even without relying on input from external sensory cues. Hippocampus 1999;9:481– 489. © 1999 Wiley-Liss, Inc.

Automatic activation of the medial temporal lobe during encoding: lateralized influences of meaning and novelty.

Abstract: In contrast to early failures, recent functional brain imaging studies have shown that medial temporal lobe (MTL) structures are active during performance of a variety of tasks. These studies have revealed three properties of the MTL that are consistent with its critical role in establishing new declarative memories. First, the MTL is automatically engaged whenever an event is experienced, with the side of activation (left, right) dependent on the nature of the material presented (verbal, nonverbal). Second, the strength or amount of activity depends on how well the material is encoded. Deep encoding will produce more MTL activity than shallow encoding. Depth of encoding-related increases in activity are more commonly seen on the left, because deep encoding is nearly always synonymous with encoding for meaning, and, therefore, depends on left-lateralized language mechanisms. Third, the amount of MTL activity depends on novelty. Unfamiliar events and contexts will produce more MTL activity than familiar events and contexts. Novelty-related increases are more commonly seen on the right, perhaps reflecting the greater role of the right hemisphere in maintaining tonic attention and arousal. These findings suggest a hemispheric division of labor involving encoding for meaning (left) and novelty detection (right), both of which lead to better remembering. Hippocampus 1999;9:62–70. © 1999 Wiley-Liss, Inc.

Impaired recognition memory on the Doors and People Test after damage limited to the hippocampal region.

Abstract: There have been conflicting reports about the importance of the hippocampal region for recognition memory. Vargha-Khadem et al. (1997) described three patients who became amnesic early in life as a result of damage apparently limited to the hippocampal region. One of these patients (Jon) performed normally on the recognition portion of the Doors and People Test but was severely impaired in recall. To compare adult-onset amnesia directly with these early-onset cases, we tested six amnesic patients on the Doors and People Test. Three of the patients have damage thought to be limited to the hippocampal region. All six patients were markedly impaired on both the recall and recognition portions of the test. To account for the difference between our adult-onset cases and the early-onset case (Jon), we suggest that some compensation for Jon's injury occurred during development, either due to functional reorganization of cortex adjacent to the hippocampus or as the result of learned strategies. Hippocampus 1999;9:495–499. © 1999 Wiley-Liss, Inc.

Hippocampectomized rats are impaired in homing by path integration.

Abstract: Theoretical, behavioral, and electrophysiologic evidence suggests that the hippocampal formation may play a role in path integration, a form of spatial navigation in which an animal can return to a starting point by integrating self-movement cues generated on its outward journey. The present study examined whether the hippocampus (Ammon's horn and the dentate gyrus) is involved in this form of spatial behavior. Control rats and rats with selective ibotenic acid lesions of the hippocampus were tested in a foraging task in which they retrieved large food pellets from an open field, which when found, they carried to a refuge for consumption. The experiments measured the rats' homing accuracy, returning to the starting location, under conditions in which visual, surface, and self-movement cues; surface and self-movement cues; or only self-movement cues were available. Although both control rats and rats without a hippocampus could use visual and surface cues, only control rats appeared to be able to use self-movement cues. The finding that hippocampal rats are impaired under conditions requiring the use of self-movement cues suggests that the hippocampus plays an essential role in path integration. Hippocampus 1999;9:553–561. © 1999 Wiley-Liss, Inc.

Hippocampal encoding of non-spatial trace conditioning.

Abstract: Trace eyeblink classical conditioning is a non-spatial learning paradigm that requires an intact hippocampus. This task is hippocampus-dependent because the auditory tone conditioned stimulus (CS) is temporally separated from the corneal airpuff unconditioned stimulus (US) by a 500-ms trace interval. Our laboratory has performed a series of neurophysiological experiments that have examined the activity of pyramidal cells in the CA1 area of the hippocampus during trace eyeblink conditioning. We have found that the non-spatial stimuli involved in this paradigm are encoded in the hippocampus in a logical order that is necessary for their association and the subsequent expression of behavioral learning. Although there were many profiles of single neurons responding to the CS-US trial during training, the majority of the neurons showed an increase in activity to the airpuff-US. Prior to learning, it appears that hippocampal cells and ensembles of cells were preferentially attending to the stimulus with immediate behavioral importance, the US. Hippocampal cells then began to respond to the associated neutral stimulus, the CS. Shortly thereafter, animals began to show increases in the behavioral expression of CRs. In some experiments, hippocampal neurons from aged animals exhibited impairments in the encoding of CS and US information. These aged animals were not able to associate these stimuli and acquire trace eyeblink CRs. Our findings along with the findings of other spatial learning studies, suggest that the hippocampus is involved in encoding information about discontiguous sets of stimuli, either spatial or nonspatial, especially early in the learning process.

Complimentary roles for hippocampal versus subicular/entorhinal place cells in coding place, context, and events.

Abstract: At least two important questions are posed by the existence of hippocampal place cells. The first of these has to do with how the complex, abstract properties exhibited by these cells can be explained mechanistically. The second has to do with the implications of place cells for our conception of the broader role of the hippocampus in spatial and other behaviors. Here, evidence is reviewed that: (1) Hippocampal cells show different "maps" (place cell representations) for each environment the animal visits and, in fact, can show multiple maps even for any one environment. The choice of the current map for any one environment depends on environmental, contextual, and event-related variables. (2) Cells in the subiculum and entorhinal cortex also show location-specific firing patterns (like hippocampal place cells), but show the same pattern for each environment the animal visits. A model is presented that is a variant of hippocampus-based path integration models developed by McNaughton and colleagues. In this version, the subiculum and entorhinal cortex work together to form a single, universal map that is used for each environment, and that can exhibit path integration abilities. The universal subicular/entorhinal representation is postulated to assist the hippocampal layer to rapidly form new environment and context specific "maps" for each new environment/temporal context ("episode") the animal experiences. In this view, hippocampal layer activity is always obligatorily spatial, due to the input from the entorhinal universal "map." However, the fact that the hippocampus generates a new map in response to global, non-spatial, contextual attributes of each situation, means that the hippocampus is always coding non-spatial aspects of a situation using its obligatorily spatial code. This brings the hippocampal place cell activity in to line with the broader role that has been postulated for the hippocampus in learning and memory functions.

Temporally-specific retrograde amnesia in two cases of discrete bilateral hippocampal pathology.

Abstract: The role of the hippocampus in retrograde amnesia re- mains controversial and poorly understood. Two cases are reported of discrete bilateral hippocampal damage, one of which was a rare case of limbic encephalitis secondary to the human herpes virus 6. Detailed memory testing showed marked anterograde memory impairment, but only mild, temporally-limited retrograde amnesia that covered a period of several years in both autobiographical and factual knowledge domains. The absence of extensive retrograde amnesia in these two cases points to a time-limited role for the hippocampus in the retrieval of retrograde memories, and suggests that entorhinal, perirhinal, parahippocampal, or neocortical areas of the temporal lobe may be more critical than the hippocampus proper for long-term retrograde memory functioning. Our findings offer general support to theories of memory consolidation that propose a gradual transfer of memory from hippocampal to neocortical dependency. Hippocampus 1999; 9:247-254. r 1999 Wiley-Liss, Inc.

Neonatal aspiration lesions of the hippocampal formation impair visual recognition memory when assessed by paired‐comparison task but not by delayed nonmatching‐to‐sample task

Abstract: Previous experiments showed that neonatal aspiration lesions of the hippocampal formation in monkeys yield no visual recognition loss at delays up to 10 min, when recognition memory was assessed by a trial-unique delayed nonmatching-to-sample (DNMS) task. The present study examined whether neonatal hippocampal lesions also have no effect on visual recognition when assessed by a visual paired-comparison (VPC) task. In the VPC task, animals are looking at visual stimuli and their preference for viewing new stimuli is measured. Normal adult monkeys showed strong preference for looking at the novel stimuli at all delays tested. By contrast, adult monkeys with neonatal hippocampal lesions, which included the dentate gyrus, cornus ammon (CA) fields, subicular complex, and portions of parahippocampal areas TH/TF, showed preference for novelty at short delays of 10 s but not at longer delays of 30 s to 24 h. This visual recognition loss contrasts with the normal performance of the same operated animals when tested in the DNMS task. The discrepancy between the results obtained in the two recognition tasks suggests that, to perform normally on the DNMS task, the operated monkeys may have used behavioral strategies that do not depend on the integrity of the hippocampal formation. In this respect, VPC appears to be a more sensitive task than DNMS to detect damage to the hippocampal region in primates. Hippocampus 1999;9:609–616. © 1999 Wiley-Liss, Inc.

Hippocampal Representational Organization and Spatial Context

Abstract: The hippocampus appears to undergo continual representa- tional reorganization as animals navigate their environments. This reorga- nization is postulated to be reflected spatially in terms of changes in the ensemble of place cells activated, as well as changes in place field specificity and reliability for cells recorded in both hilar/CA3 and CA1 regions. The specific contribution of the hilar/CA3 region is suggested to be to compare the expected spatial context with that currently being experienced, then relay discrepancies to CA1. The properties of CA1 place fields in part reflect the spatial comparisons made in the hilar/CA3 area. In addition, CA1 organizes the input received from the hilar/CA3 place cells according to different temporal algorithms that are unique to different tasks. In this way, hippocampus helps to distinguish temporally one spatial context from another, thereby contributing to episodic memories. Hippo- campus 1999;9:444-451. r 1999 Wiley-Liss, Inc.

Role of the hippocampal system in conditional motor learning: mapping antecedents to action.

Abstract: Macaque monkeys can learn arbitrary mappings between stimuli and spatially directed actions (often termed conditional motor learning), and, after the development of a strong learning set, can do so in just a few trials. Ablation studies have shown that the hippocampus plus subjacent cortex is necessary for this rapid and highly flexible type of learning. We consider evidence that the arbitrary mapping function of the hippocampal system may be more general and fundamental than currently accepted and what limitations there may be, if any, on the information that it can map. Removal of the hippocampal system yields a pattern of deficits and preserved abilities that correlates remarkably closely with that found in human global amnesics, such as patient H.M., on a variety of declarative memory tasks. Thus, the rapid acquisition of arbitrary visuomotor mappings may represent an example of declarative memory in nonhuman primates.

Level of sustained entorhinal activity at study correlates with subsequent cued-recall performance: a functional magnetic resonance imaging study with high acquisition rate.

Abstract: Functional magnetic resonance imaging (fMRI) with high acquisition rate was performed during the intentional memorizing of words to specify which medial temporal lobe structure is important in determining what words are subsequently remembered in a cued-recall test and to characterize the time course of activation in that structure. Functional images of six healthy young subjects were analyzed by two subject- and voxel-wise statistics: First, to identify brain areas transiently engaged in encoding of words, brain activity during memorizing visually presented words and watching a fixation cross was compared by a Kolmogorov-Smirnov statistic (KS-test). Second, to identify brain areas whose activity correlates with memory encoding success, a Kendall's correlation was calculated between signal intensity at study and performance in a subsequent cued-recall test. Averaged signal intensities were plotted as a function of time to depict the time course of brain activity detected by both statistical tests. The level of slowly modulated, sustained activity in Brodmann area 28 (entorhinal cortex) did not respond transiently as study words appeared, but did correlate positively with subsequent test performance. More left than right activity in Brodmann area 45 (dorso-lateral prefrontal cortex) and bilateral activity in Brodmann area 44 (premotor cortex) exhibited transient hemodynamic responses that did not show any relation to subsequent memory performance. Thus, the study identified a novel pattern of slowly modulated brain activity in human entorhinal cortex that may represent a declarative memory encoding state whose level predicts whether experiences will be remembered or forgotten. Hippocampus 1999;9:35–44. © 1999 Wiley-Liss, Inc.

Morphometry of a peptidergic transmitter system: dynorphin B-like immunoreactivity in the rat hippocampal mossy fiber pathway before and after seizures.

Abstract: While the morphometry of classical transmitter systems has been extensively studied, relatively little quantitative information is available on the subcellular distribution of peptidergic dense core vesicles (DCVs) within axonal arbors and terminals, and how distribution patterns change in response to neural activity. This study used correlated quantitative light and electron microscopic immunohistochemistry to examine dynorphin B-like immunoreactivity (dyn B-LI) in the rat hippocampal mossy fiber pathway before and after seizures. Forty-eight hours after seizures induced by two pentylenetetrazol injections, light microscopic dyn B-LI was decreased dorsally and increased ventrally. Ultrastructural examination indicated that, in the hilus of the dentate gyrus, these alterations resulted from changes that were almost entirely restricted to the profiles of the large mossy-like terminals formed by mossy fiber collaterals (which primarily contact spines), compared to the profiles of the smaller, less-convoluted terminals found on the same collaterals (which primarily contact aspiny dendritic shafts). Dorsally, mossy terminal profile labeled DCV (lDCV) density dropped substantially, while ventrally, both mossy terminal profile perimeter and lDCV density increased. In all terminal profiles examined, lDCVs also were closely associated with the plasma membrane. Following seizures, there was a reorientation of lDCVs along the inner surface of mossy terminal profile membranes, in relation to the types of profiles adjacent to the membrane: in both the dorsal and ventral hilus, significantly fewer lDCVs were observed at sites apposed to dendrites, and significantly more were observed at sites apposed to spines. Thus, after seizures, changes specific to: (1) the dorsoventral level of the hippocampal formation, (2) the type of terminal, and (3) the type of profile in apposition to the portion of the terminal membrane examined were all observed. An explanation of these complex, interdependent alterations will probably require evoking multiple interrelated mechanisms, including selective prodynorphin synthesis, transport, and release. Hippocampus 1999; 9:255–276. © 1999 Wiley-Liss, Inc.

Hippocampal lesions interfere with Pavlovian negative occasion setting

Abstract: Rats were trained with either a serial feature positive (L-->T1+ T-) or a serial feature negative (L-->T1-, T1+) discrimination, intermixed with training on another, nonconditional discrimination (T2+, N-), using a Pavlovian appetitive conditioning preparation with multiple response measures. Among rats trained with the serial feature positive discrimination, neurotoxic lesions of the hippocampus produced a transient impairment in the acquisition of that discrimination, but did not affect acquisition of the nonconditional discrimination. In contrast, among rats that received serial feature negative discrimination training, hippocampal lesions produced enduring deficits in the acquisition of both discriminations. The results of transfer tests indicated that both lesioned and control rats used a conditional learning strategy (occasion setting) to solve the feature positive and feature negative discriminations. Furthermore, lesioned rats, especially those that received training with the feature negative discrimination, displayed increasingly higher levels of general activity as training progressed. The results suggest that hippocampal lesions particularly interfere with inhibitory learning (negative occasion setting) about both explicit and contextual cues.

Hippocampal place cells can develop distinct representations of two visually identical environments.

Abstract: The pattern separation ability of hippocampal place cells was tested in an environment in which two visually identical rectangular compartments (Box A and Box B) were connected by a hidden door. Small ensembles of neurons were recorded with tetrodes while the rat searched for randomly distributed loci for reinforcing brain stimulation. The first recording session in Box A was conducted after the rat had explored the environment for the first time for 30 min. Immediately thereafter, a hidden door between Box A and Box B was opened to let the rat into the unexplored compartment, and a 5-min recording session was run with the door concealed. A rearrangement of place fields in Box B was observed in 18/20 neurons and in 5/6 ensembles. Most place fields did not change between two successive sessions in Box B. When the rat returned to Box A, the ensembles of neurons were as likely to adopt the original Box A firing field pattern as the more recent Box B pattern. In order to control for the influence of extra-arena cues, the rat was gradually lifted in a closed bucket from Box A into Box B while the whole arena was rotated by 90°. All but one neuron and all the ensembles followed the intra-arena cues. Both rotated Box B and Box A firing field patterns were represented but Box B pattern was stronger among the neuronal ensembles. These findings indicate that hippocampal place cells not only can develop distinct representations of two visually identical environments but also can selectively reactivate either one of these representations depending on the rat's recent experience. Hippocampus 1999;9:235–246. © 1999 Wiley-Liss, Inc.

Synaptogenesis of mossy fibers induced by spatial water maze overtraining.

Abstract: Synaptic plasticity has been proposed as a mechanism underlying learning and memory. Synaptic reorganization of hippocampal mossy fibers has been observed after experimentally induced epilepsy, and after brief high-frequency activation inducing long-term potentiation. Furthermore, it has been suggested that synaptic changes in the hippocampus may occur after spatial learning. In this study, by using a zinc-detecting histologic technique (Timm), we demonstrate a significant increase of mossy fiber terminals in the CA3 stratum oriens region induced by training rats during 3 days in a spatial Morris water maze. In contrast, animals trained for only 1 day and animals that were just allowed to swim or were overtrained in a stress-motivated inhibitory avoidance task did not show increments of mossy fiber terminals in the stratum oriens. Electron microscopy confirmed that synaptic density of mossy fiber terminals in the stratum oriens increases significantly in water maze overtrained animals compared with the swimming control animals. Taken together, these results suggest that overtraining in a spatial learning task induces mossy fiber synaptogenesis that could be involved in the mechanisms underlying long-term memory storage. Hippocampus 1999;9:631-636.

Positron emission tomography correlations in and beyond medial temporal lobes

Abstract: This article discusses the potential usefulness of brain/ behavior correlational analyses in functional neuroimaging studies of memory, and how such analyses can illuminate the role of medial temporal lobes (MTL) and the hippocampus in episodic and declarative memory processes such as encoding and retrieval. Reanalysis of the results of four previously reported positron emission tomography (PET) studies yielded evidence of both positive and negative between-subjects correlations between recogni- tion-memory accuracy and regional blood flow. The sites of these correlations were in MTL regions as well as in other cortical and subcortical areas, including frontal lobes (Brodmann areas 6, 9, 10, 11, and 47), temporal lobes (BAs 21, 22, and 38), insula, fusiform gyrus, and cuneus/precuneus. These findings were discussed with respect to issues such as localization of the correlation sites, the distinction between brain sites revealed by brain/cognition correlational analyses (''how'' sites) and those yielded by cognitive subtraction methods (''what'' sites), the tendency of the ''how'' sites in MTL to occur in the left hemisphere, the tendency of other ''how'' sites to occur in one or the other hemisphere, rather than bilaterally, and the meaning and ''reality'' of both brain/behavior correlations and task-related activations. Because of the known incidence of false-positives, all neuroimaging data, including those involving the localization of ''what'' and ''how'' memory sites in MTL and other brain regions, need to be interpreted cautiously, and findings of individual studies should not be overinterpreted. Hippocampus 1999;9:71-82. r 1999 Wiley-Liss, Inc.