Paul E. Gilbert

The role of the hippocampus in memory for the temporal order of a sequence of odors.

Memory for the temporal order of a sequence of odors was assessed in rats. A sequence of 5 odors mixed in sand was presented in digging cups, 1 at a time, to each rat in a sequence that varied on each trial. A reward was buried in each cup. After the 5th odor, 2 of the previous 5 odors were presented simultaneously; to receive a reward, the rat had to choose the odor that occurred earliest in the sequence. Temporal separations of 1, 2, or 3 represented the number of odors that occurred between the 2 odors in the sequence. Once a preoperative criterion was reached, each rat received a hippocampal (HIP) or cortical control lesion and was retested on the task. On postoperative trials, the HIP group was impaired relative to controls. However, the HIP group could discriminate between the odors. The data suggest that the hippocampus is involved in separating sensory events in time so that I event can be remembered separately from another event.

Visual Object Pattern Separation Deficits in Nondemented Older Adults.

Young and nondemented older adults were tested on a continuous recognition memory task requiring visual pattern separation. During the task, some objects were repeated across trials and some objects, referred to as lures, were presented that were similar to previously presented objects. The lures resulted in increased interference and an increased need for pattern separation. For each object, the participant was asked to indicate whether (1) this was the first time the object was seen (new), (2) the object was seen previously (old), or (3) the object was similar to a previous object (similar). Older adults were able to correctly identify objects as old or new as well as young adults; however, older adults were impaired when identifying lures as similar. Therefore, pattern separation may be less efficient in older adults resulting in poorer recognition memory performance when interference is increased.

Localization of function within the dorsal hippocampus: The role of the CA3 subregion in paired-associate learning

Computational models and electrophysiological data suggest that the CA3 subregion of the hippocampus supports the formation of arbitrary associations; however, no behavioral studies have been conducted to test this hypothesis. Rats with neurotoxin-induced lesions of dorsal dentate gyrus (DG), CA3, or CA1 were tested on object-place and odor-place paired-associate tasks to test whether the mechanism that supports paired-associate learning is localized to the CA3 subregion of the dorsal hippocampus or whether all hippocampal subregions contribute to paired-associate learning. The data indicate that rats with DG or CA1 lesions learned the tasks as well as controls; however, CA3-lesioned rats were impaired in learning the tasks. Thus, the CA3 subregion of the dorsal hippocampus contains a mechanism to support paired-associate learning.

Role of rodent hippocampus in paired-associate learning involving associations between a stimulus and a spatial location.

The ability of rats with control or hippocampal lesions to learn an object-place, odor-place, or object-odor paired-associate task was assessed in a cheeseboard maze apparatus. The data indicate that rats with hippocampal lesions were significantly impaired, compared with controls, in learning both the object-place and the odor-place paired-associate tasks. However, rats with hippocampal lesions learned the object-odor paired-associate task as readily as did controls. The data suggest that the rodent hippocampus is involved in paired-associate learning when a stimulus must be associated with a spatial location. However, the hippocampus is not involved in paired-associate learning when the association does not involve a spatial component.

The role of the dorsal CA3 hippocampal subregion in spatial working memory and pattern separation.

A delayed-match-to-sample for spatial location task was used to measure spatial pattern separation and working memory. On each trial, an object covered a baited food well in one of 15 spatial locations along a row of food wells perpendicular to the start box. Once the rat exited the start box, displaced the object to receive a food reward and then returned to the startbox, the same food well was then quickly re-baited, an identical object was positioned to cover the food well and another identical object was positioned in a different location along the row of food wells covering a different unbaited food well. On the ensuing choice phase, the animal was allowed to choose between the two objects. The object that covered the same food well as the object in the sample phase was the correct choice and the second foil object was the incorrect choice. Five spatial separations (15-105 cm) were randomly used to separate the correct object from the foil object during the choice phase. Once a preoperative criterion was met, each rat received bilateral intracranial infusions of either ibotenic acid or the vehicle into the CA3 subregion of the dorsal hippocampus. Following surgery, rats with CA3 lesions were significantly impaired relative to controls across all spatial separations suggesting that CA3 lesions impaired working memory. Although the dorsal CA3 subregion of the hippocampus may play a role in pattern separation, the data suggest that this region is critically involved in spatial working memory.

The role of CA1 in the acquisition of an object-trace-odor paired associate task.

This experiment was designed to determine whether adding a temporal component to an object-odor association task would recruit the hippocampus. The rats were given CA1, CA3, or control lesions prior to learning the object-trace-odor task. Rats were presented with an object for 10 s, after which the object was removed, followed by a 10-s trace period, followed by the presentation of an odor 50 cm away. If the odor and the object were paired, rats were to dig in the odor cup for a reward. If unpaired, rats were to refrain from digging. Rats that had CA1 lesions were unable to make the association, whereas rats that had CA3 lesions performed as well as controls. These results support the idea that the hippocampus is involved in forming arbitrary associations that do not necessarily involve space as long as they involve a temporal component.

The role of the CA3 hippocampal subregion in spatial memory: A process oriented behavioral assessment

Computational models, behavioral data, and electrophysiological data suggest that the CA3 subregion of the hippocampus may support multiple mnemonic processes critical to the formation and subsequent retrieval of spatial memories. Multiple researchers have proposed that the CA3 subregion contains an autoassociative network in which synaptic connections between CA3 neurons that represent different components of a memory are strengthened via recurrent collateral connections. As a result, it has been suggested that the CA3 autoassociative network may support multiple processes including the formation of spatial arbitrary associations, temporary maintenance of spatial working memory, and spatial pattern completion. In addition, the CA3 subregion has been suggested to be involved in spatial pattern separation. The separation of patterns is hypothesized to be accomplished based on the low probability that any two CA3 neurons will receive mossy-fiber input synapses from a similar subset of dentate gyrus cells. The separation of patterns also may be enhanced by competitive inhibition within CA3 and dentate gyrus. This review will focus on the mnemonic processes supported by CA3 neurons and how these processes may facilitate the encoding and retrieval of spatial information. Although there is growing evidence indicating that the hippocampus plays a role in the processing of nonspatial information as well, the scope of the present review will focus on the role of the CA3 subregion in spatial memory.

Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations.

The hippocampus (HPP) plays a known role in learning novel spatial information. More specifically, the dentate gyrus (DG) hippocampal subregion is thought to support pattern separation, a mechanism for encoding and separating spatially similar events into distinct representations. Several studies have shown that lesions of the dorsal DG (dDG) in rodents result in inefficient spatial pattern separation for working memory; however, it is unclear whether selective dDG lesions disrupt spatial pattern separation for reference memory. Therefore, the current study investigated the role of the dDG in pattern separation using a spatial reference memory paradigm to determine whether the dDG is necessary for acquiring spatial discriminations for adjacent locations. Male Long-Evans rats were randomly assigned to receive bilateral intracranial infusions of colchicine or saline (control) into the dDG. Following recovery from surgery, each rat was pseudo-randomly assigned to an adjacent arm or separate arm condition and subsequently tested on a place-learning task using an eight-arm radial maze. Rats were trained to discriminate between a rewarded arm and a nonrewarded arm that were either adjacent to one another or separated by a distance of two arm positions. Each rat received 10 trials per day and was tested until the animal reached a criterion of nine correct choices out of 10 consecutive trials across 2 consecutive days of testing. Both groups acquired spatial discriminations for the separate condition at similar rates. However, in the adjacent condition, dDG lesioned animals required significantly more trials to reach the learning criterion than controls. The results suggest that dDG lesions decrease efficiency in pattern separation resulting in impairments in the adjacent condition involving greater overlap among the distal cues. Conversely, in the separate condition, there was less overlap among distal cues during encoding and less need for pattern separation. These findings provide further support for a critical role for the dDG in spatial pattern separation by demonstrating the importance of a processing mechanism that is capable of reducing interference among overlapping spatial inputs across a variety of memory demands.

Spatial pattern separation in cognitively normal young and older adults

This study examined the ability of cognitively normal young adults (n = 30) and older adults (n = 30) to perform a delayed match‐to‐sample task involving varying degrees of spatial interference to assess spatial pattern separation. Each trial consisted of a sample phase followed by a choice phase. During the sample phase, a circle appeared briefly on a computer screen. The participant was instructed to remember the location of the circle on the screen. During the choice phase, two circles were displayed simultaneously, and the participant was asked to indicate which circle was in the same location as the sample phase circle. The two circles on choice phase trials were separated by one of four possible spatial separations: 0, 0.5, 1.0, and 1.5 cm. Smaller separations are likely to create increased overlap among memory representations, which may result in heightened interference and a greater need for pattern separation. Consistent with this hypothesis, performance increased as a function of increased spatial separation in both young and older adults. However, young adults outperformed older adults, suggesting that spatial pattern separation may be less efficient in older adults due to potential age‐related changes in the dentate gyrus and CA3 hippocampal subregions. Older adults also were divided into older impaired and older unimpaired groups based on their performance on a standardized test of verbal memory. The older impaired group was significantly impaired relative to both the older unimpaired and young groups, suggesting that pattern separation deficits may be variable in older adults. The present findings may have important implications for designing behavioral interventions for older adults that structure daily living tasks to reduce interference, thus improving memory function.

Memory for objects and their locations: The role of the hippocampus in retention of object–place associations

Computational models of hippocampal function have suggested that the hippocampus is involved in the formation and storage of arbitrary associations. Previous studies have shown that rats with hippocampal lesions are impaired in object-place associative learning. However, few studies have examined the role of the hippocampus in the retention of previously learned arbitrary associations. In the present study, male Long-Evans rats with either cortical control or hippocampal lesions were tested on a task measuring the retention of previously learned arbitrary associations using an object-place paired-associate task. To assess retention, each animal was trained on the paired-associate task for 360 trials, then received a lesion, and was retested to examine retention of the previously learned associations. The results indicate that all rats learned the task prior to surgery. Following surgery, rats with cortical control lesions were not impaired in the retention of object-place associations. In contrast, hippocampal lesions resulted in an initial deficit in retention of the paired-associate task followed by recovery. Therefore, the hippocampus may play a role in the retrieval of previously learned arbitrary association.