Robert J. Sutherland

Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat

Abstract Unlike normal rats, rats with bilateral lesions in either the hippocampus or medial frontal cortex did not learn to swim from different directions to a hidden platform located at a specific place in a room. Experimental and clinical evidence indicates that a fronto-hippocampal system may provide an integrated neurological basis for spatial representational ability.

A characterization of performance by men and women in a virtual Morris water task:: A large and reliable sex difference

In many mammalian species, it is known that males and females differ in place learning ability. The performance by men and women is commonly reported to also differ, despite a large amount of variability and ambiguity in measuring spatial abilities. In the non-human literature, the gold standard for measuring place learning ability in mammals is the Morris water task. This task requires subjects to use the spatial arrangement of cues outside of a circular pool to swim to a hidden goal platform located in a fixed location. We used a computerized version of the Morris water task to assess whether this task will generalize into the human domain and to examine whether sex differences exist in this domain of topographical learning and memory. Across three separate experiments, varying in attempts to maximize spatial performance, we consistently found males navigate to the hidden platform better than females across a variety of measures. The effect sizes of these differences are some of the largest ever reported and are robust and replicable across experiments. These results are the first to demonstrate the effectiveness and utility of the virtual Morris water task for humans and show a robust sex difference in virtual place learning.

A comparison of the contributions of the frontal and parietal association cortex to spatial localization in rats.

Rats with lesions of the medial frontal, orbital frontal, or parietal cortex were compared behaviorally with rats with complete removal of the neocortex and normal control rats on three spatial tasks: Morris water task, radial arm maze, and spatial reversals in a Grice box. Decortication produced severe impairments in the acquisition of all three tasks, thus providing a measure against which to compare the severity of the impairments observed following more restricted removals. Rats with parietal cortex lesions were relatively unimpaired at any of the tasks, although they had a significant deficit on the spatial reversal task and had a short-term memory impairment on the radial arm maze. In contrast, rats with medial frontal lesions had a significant, but relatively mild, impairment on the radial arm maze and were very poor at learning the water task. Rats with orbital frontal lesions were nearly as impaired on the radial arm maze and water task as decorticate rats. The results suggest that the frontal and parietal cortex of rats play different roles in the control of spatial orientation but do not support the view that egocentric and allocentric spatial orientation are related to frontal and parietal mechanisms, respectively. In addition, the results suggest that the frontal cortex plays a larger role in the control of spatially guided behavior than has been previously recognized and that both the medial frontal and the orbital (sulcal) frontal cortex play a dissociable role in the control of spatial orientation.

Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge

SummaryThe effects of massive destruction of granule cells of the fascia dentata on the spatial and temporal firing characteristics of pyramidal cells in the CA1 and CA3 subfields of the hippocampus were examined in freely moving rats. Microinjections of the neurotoxin colchicine were made at a number of levels along the septo-temporal axis of the dentate gyri of both hemispheres, resulting in destruction of over 75% of the granule cells. By contrast there was relatively little damage to the pyramidal cell fields. As assessed by three different behavioral tests, the colchicine treatment resulted in severe spatial learning deficits. Single units were recorded from the CA1 and CA3 subfields using the stereotrode recording method while the animals performed a forced choice behavioral task on the radial 8-arm maze. Considering the extent of damage to the dentate gyrus, which has hitherto been considered to be the main source of afferent information to the CA fields, there was remarkably little effect on the spatial selectivity of “place cell” discharge on the maze, as compared to recordings from control animals. There was, however, a change in the temporal firing characteristics of these cells, which was manifested primarily as an increase in the likelihood of burst discharge. The main conclusion derived from these findings is that most of the spatial information exhibited by hippocampal pyramidal cells is likely to be transmitted from the cortex by routes other than the traditional “trisynaptic circuit”. These routes may include the direct projections from entorhinal layers II and III to CA3 and CA1, respectively.

Humans with hippocampus damage display severe spatial memory impairments in a virtual Morris water task

For nonhumans, it has been shown that the hippocampus (HPC) is critical for spatial memory. We tested patients with unilateral HPC resections on a virtual analogue of a classic spatial task to assess HPC functioning in nonhumans: the Morris water task. We found that when humans are required to use spatial cues to navigate to a hidden escape platform in a pool, patients with HPC resections display severe impairments in spatial navigation relative to age-matched controls and age-matched patients who have had extra-HPC resections. This effect occurred for every patient tested and was evident regardless of side of surgery. Hence, it is apparent across species and irrespective of which hemisphere is damaged that the human HPC is critical for spatial/relational memory.

The hippocampal formation is necessary for rats to learn and remember configural discriminations

A negative patterning discrimination problem was arranged by reinforcing rats for bar pressing when either a light or tone was presented (L+/T+) but not reinforcing the response when the compound stimulus, light and tone, was presented (LT-). To solve this problem, the animal must be able to construct a unique configural representation of the compound that can be distinguished from the representations of the individual elements. We have proposed that the hippocampal formation is essential for the acquisition and retention of associations involving configural representations. Thus, our theory predicts that animals with hippocampal formation damage will not learn the negative patterning problem and that animals who learned this problem before receiving hippocampal formation damage will not retain the solution. These predictions were confirmed by the results of two experiments. The animals with hippocampal formation damage were unable to solve the negative patterning problem. These animals were able to solve a simple discrimination in which responding in the presence of a light was rewarded but responding in the presence of a tone was not rewarded. These results are discussed in relation to several other theories of hippocampal formation function.

Virtual navigation in humans: the impact of age, sex, and hormones on place learning.

Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age >60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.

Hippocampus, amygdala, and memory deficits in rats

Five experiments were conducted to compare the contribution of the hippocampal formation and amygdala to mnemonic processes. The performance of rats with damage to the hippocampal formation or amygdala was examined in tests of visual and olfactory non-matching-to-sample with familiar items, cross-modal association, gustatory neophobia, topographical memory, autonomic conditioning to context, and configural discriminations. Neither lesion affects non-matching-to-sample performance. An intact hippocampal formation, but not amygdala, is necessary for cross-modal association between vision and olfaction, topographical memory, conditioning to context, and configural discrimination learning. Amygdala damage disrupted gustatory neophobia and may have impaired learning an association between an auditory cue and food reward.

Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task

We employed a computerized (virtual) Morris water task (VMWT) to measure place learning and cued-navigation in eight adolescent males (9.5-16.5 years old) diagnosed with Fetal Alcohol Syndrome (FAS). Eight adolescent males matched for age and ethnicity with no history of prenatal alcohol exposure served as controls. Participants were trained to navigate to a hidden platform in a fixed location relative to a set of four conspicuous extramaze cues. After 20 hidden platform trials, a single no-platform probe trial was conducted, followed by 8 trials during which the platform was visible (cued-navigation). The FAS group traveled further than controls to navigate to the hidden platform during training. During the probe trial, controls navigated more directly to the platform region and persisted in searching where the platform had been more than the FAS group. Cued-navigation was comparable in both groups, suggesting that group differences in place learning were not attributable to visual-motor or motivational deficits in the FAS subjects. This pattern of impaired place learning and spared cued-navigation is similar to that reported in rats exposed to ethanol during periods of prenatal or early postnatal brain growth, as well as in animals with hippocampal damage.

The aging hippocampus: a multi-level analysis in the rat.

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.