Hippocampal Formation Damage Research Articles

Fimbria-fornix lesions disrupt the dead reckoning (homing) component of exploratory behavior in mice.

Exploration is the primary way in which rodents gather information about their spatial surroundings. Thus, spatial theories propose that damage to the hippocampus, a structure thought to play a fundamental role in spatial behavior, should disrupt exploration. Exploration in rats is organized. The animals create home bases that are central to exploratory excursions and returns, and hippocampal formation damage alters the organization of exploration by disrupting returns. Mice do not appear to readily establish home bases in novel environments, thus, for this species, it is more difficult to establish the contribution of the hippocampus to exploration. The purpose of the present study was threefold: develop a task in which mice center their exploration from a home base, determine whether the exploratory behavior is organized, and evaluate the role of fimbria-fornix lesions on exploration. Mice were given a novel exploratory task in which their nesting material was placed on a large circular table. Video records of control and fimbria-fornix mice were made in both light and dark (infrared light) conditions. Exploration patterns (outward trips, stops, and homeward trips) were reconstructed from the video records. Control mice centered their activity on their bedding, from which they made circuitous outward trips marked by many stops, and periodic direct returns. The bedding-centered behavior and outward trips of the fimbria-fornix mice were similar to those of the control mice, but significantly fewer direct return trips occurred. The direct homeward trips observed under light and dark conditions were consistent with a dead-reckoning strategy, in which an animal computes its present position and homeward trajectory from self-movement cues generated on the outward trip. Because the fimbria-fornix lesions disrupted the homeward component of exploratory trips, we conclude that the fimbria-fornix may contribute to dead reckoning in mice. The results also show that the home-bedding methodology facilitates the establishment of a home base by mice, thus providing a useful methodology for studies with mice.

Quantification of a single exploratory trip reveals hippocampal formation mediated dead reckoning

A rat's proclivity to explore a novel environment presents a behaviorally rich paradigm to investigate the role of the hippocampus in spatial navigation. Here we describe a novel technique of behavioral analysis that is derived from a single exploratory trip. An exploratory trip was defined as a rat's departure from the home base that ended when the rat returned to the home base. The behavior observed on a single exploratory trip by a control animal is highly organized into outward and homeward segments. An outward segment is characterized by a slow circuitous progression from the home base marked by several stops. A homeward segment is characterized by a rapid direct return to the home base. The velocity attribute of the exploratory trip was quantified by estimating the point of inflection associated with the trip's cumulative moment-to-moment velocity distribution. The heading direction and variance of the homeward trip segment was analyzed with circular statistics. A comparison of the exploratory behavior of control animals and animals with damage to the fimbria-fornix indicated that the velocity and heading direction of the homeward portion of the trip depends upon the hippocampal formation. While control and fimbria-fornix rats had similar outward segments, the return paths of the fimbria-fornix rats were significantly slower, more circuitous, and more variable compared with that of the control rats. This result was also independent of testing in light or dark conditions. The lack of dependence on allothetic cues suggests that rats employ dead reckoning navigational strategies to initiate the homeward portion of exploratory movements. Methods to quantify exploratory behavior in terms of velocity and angular components provide an assessment of control behavior and the assessment of the behavior of rats with hippocampal formation damage that is easy to implement.

Spatial mapping takes time.

The experiment tested the prediction that spatial mapping takes time and asked whether time use is reflected in the overt behavior of a performing animal. The study examines this question by exploiting the expected behavioral differences of control rats and rats with hippocampal formation damage induced with fimbria-fornix (FF) lesions on a spatial navigation task. Previous studies have shown that control rats use a mapping strategy, in which they use the relative positions of environmental cues to reach places in space, whereas FF rats use a cue-based strategy, in which they are guided by a single cue or their own body orientation. Therefore, control and FF rats were overtrained on a complex foraging task in which they left a burrow to retrieve eight food pellets hidden around the perimeter of a circular table. The control rats retrieved the food pellets in order of their distance from the burrow, took direct routes to the food, and made few errors, all of which suggested they used a spatial strategy. The FF rats were less likely to retrieve food as a function of its distance, took a circular path around the perimeter of the table, and made many errors, suggesting they used a cue-based strategy. Despite taking shorter routes than the FF rats, the control rats had proportionally slower response speeds. Their slow response speeds support the hypothesis that spatial mapping takes time and that mapping time is reflected in behavior. The results are discussed in relation to their relevance to spatial mapping theory, hippocampal function, and the evolution of foraging strategies.

Spatial mapping takes time

The experiment tested the prediction that spatial mapping takes time and asked whether time use is reflected in the overt behavior of a performing animal. The study examines this question by exploiting the expected behavioral differences of control rats and rats with hippocampal formation damage induced with fimbria–fornix (FF) lesions on a spatial navigation task. Previous studies have shown that control rats use a mapping strategy, in which they use the relative positions of environmental cues to reach places in space, whereas FF rats use a cue-based strategy, in which they are guided by a single cue or their own body orientation. Therefore, control and FF rats were overtrained on a complex foraging task in which they left a burrow to retrieve eight food pellets hidden around the perimeter of a circular table. The control rats retrieved the food pellets in order of their distance from the burrow, took direct routes to the food, and made few errors, all of which suggested they used a spatial strategy. The FF rats were less likely to retrieve food as a function of its distance, took a circular path around the perimeter of the table, and made many errors, suggesting they used a cue-based strategy. Despite taking shorter routes than the FF rats, the control rats had proportionally slower response speeds. Their slow response speeds support the hypothesis that spatial mapping takes time and that mapping time is reflected in behavior. The results are discussed in relation to their relevance to spatial mapping theory, hippocampal function, and the evolution of foraging strategies. Hippocampus 1998;8:122–130. © 1998 Wiley-Liss, Inc.

Electrolytic Lesions of the Fimbria/Fornix, Dorsal Hippocampus, or Entorhinal Cortex Produce Anterograde Deficits in Contextual Fear Conditioning in Rats

Recent data indicate that dorsal hippocampal (DH) lesions disrupt Pavlovian fear conditioning to contextual cues in rats. In the present study, we examined the effects of electrolytic lesions of the fimbria/fornix (FX) or entorhinal cortex (EC), the primary afferent projection systems to the DH, on contextual fear conditioning in rats. Conditioning consisted of the delivery of unsignaled footshocks in a novel observation chamber, and freezing served as the measure of conditional fear. Electrolytic lesions of the FX, DH, or EC made 1 week before training produced anterograde impairments in both immediate postshock freezing on the conditioning day and freezing during the context extinction test 24 h following training. The deficits in conditional freezing produced by FX, DH, and EC lesions were not statistically different, although the deficits in rats with FX or EC lesions tended to be more severe than those in rats with DH lesions. In addition to producing deficits in conditional freezing, FX, DH, or EC lesions produced a pronounced locomotor hyperactivity. Within the lesion and sham groups, however, locomotor activity was not significantly correlated with conditional freezing. These results indicate that contextual fear deficits in rats with hippocampal formation damage are equivalent following either FX, DH, or EC lesions. The relationship of freezing deficits and locomotor hyperactivity in rats with hippocampal formation lesions is discussed.

A comparison of kainic acid plus colchicine and ibotenic acid-induced hippocampal formation damage on four configural tasks in rats.

A comparison of kainic acid plus colchicine and ibotenic acid-induced hippocampal formation damage on four configural tasks in rats.

Configural association theory and the hippocampal formation: an appraisal and reconfiguration.

Sutherland and Rudy ([1989] Psychobiology 17:129-144) proposed that the hippocampal system is critical to normal learning and memory because of its function as the central part of a configural association system. This system constructs a unique representation of the joint occurrence of the independent elements of a compound. There is evidence consistent with the theory's predictions, however, there also are data that unambiguously demonstrate that, under some conditions, animals lacking an intact hippocampal system acquire configural associations. Thus, Sutherland and Rudy's fundamental assumption cannot be correct. To integrate the supporting and contradictory data, we propose two simple modifications of our position: 1) The critical neural system for configural associations is in cortical circuitry outside the hippocampus, and 2) the output from the hippocampal formation contributes to configural processing by selectively enhancing, thereby making more salient, cortical units representing stimulus conjunctions. This enhancement has two important effects: 1) It decreases the similarity between the configural units representing the co-occurrence of cues and the units representing the cues, and 2) It increases the rate at which the configural units can acquire associative strength. The modified theory explains why damage to the hippocampal formation only impairs learning on a subset of nonlinear discrimination problems. It also integrates recent data on the effects of hippocampal formation damage on conditioning involving context cues and makes novel predictions about performance on nonlinear discrimination problems and place learning.

Cross-modal matching performance in amnesia.

A recent neuropsychological study of patients with postencephalitic amnesia raised the possibility that limbic regions within the medial temporal lobe might be important for forming cross-modal associations. The present study evaluated cross-modal matching in amnesic patients with damage to the hippocampal formation or the diencephalon. The patients with hippocampal formation damage were fully intact at cross-modal matching (both tactile to visual and visual to tactile). Two additional (non-Korsakoff's) patients with diencephalic amnesia also performed normally at cross-modal matching. Finally, patients with Korsakoff's syndrome did not exhibit a cross-modal deficit, but they did perform poorly in some task conditions— specifically, when a stimulus examined factually had to be matched to a visual stimulus. The results indicate that severe memory impairment can occur without affecting cross-modal performance.

Hippocampal lesions do not impair negative patterning: a challenge to configural association theory.

According to configural association (CAS) theory (Sutherland & Rudy, 1989), an intact hippocampus is required for rats to solve learning problems that are based on "configural" processes. This theory identifies the negative patterning discrimination as a critical example of this type of problem. Rudy and Sutherland (1989) reported disruption of negative patterning following hippocampal formation damage produced by intracranial infusion of a mixture of kainic acid + colchicine (KA + COL). We assessed acquisition of negative patterning in rats with hippocampal damage produced by KA + COL compared with rats with more selective ibotenate lesions of hippocampus. Neither group showed impaired negative patterning relative to controls. A transfer test provided evidence that all groups used configural processes to solve the problem. Thus contrary to CAS theory, the hippocampus is not an important substrate for the operation of configural processes.

Neuroanatomical connections and specific regional vulnerability in Alzheimer's disease

PATHOLOGICAL changes associated with Alzheimer's disease (AD) occur in a consistent distribution, severely affecting certain neuronal populations in limbic areas and association cortices. De Lacoste and White (9) argue that the basis of this pattern lies in the connectional relationship among affected neurons. Indeed, in many instances, neurofibrillary tangles occur in projection neurons and senile plaques are found in termination zones. However, there are also counter-examples to this postulate. We suggest that, although disruption of these neural system connections probably underlies cognitive impairment in AD, the basis of selective neuronal vulnerability reflects an interaction between connectivity and specific molecular phenotypes in different brain regions. Whether the development of neurpathological changes associated with AD follows a predictable pattern is a critical issue in understanding the progression of the disease. The model of cortical disconnection and vulnerability due to cortical connectivity, described here by de Lacoste and White (9), proposes that pathological changes in certain brain regions can spread to other regions by well-defined cortical connections. The nature of this spread could be through the transfer of toxins or viruses, or through the disruption of interneuronal connections that normally help maintain neuronal viability. Furthermore, de Lacoste and White identify the interconnected regions of the limbic system and the temporo-occipital cortices as structures suited to test whether the AD-related changes spread from one region of the brain to another. It is important to divide the disconnection~connectivity model of AD into two components. The first is that disruption of connections of neural systems accounts for the clinical manifestations of AD. There are several pieces of data that support this assertion. First, the memory deficit of AD patients could be explained by the disruption of the connections of the hippocampus, amygdala, and entorhinal cortex by the presence of senile plaques (SP's) and neurofibrillary tangles (NFT's). These changes in the medial temporal lobe are the first alterations found in the brains of patients with AD (2,19,20,33) and are consistent with the primacy of memory loss in patients with AD. Second, the distribution and degree of neuropathological changes correlates, at least in some studies, with measures of dementia (2,27,37). Third, the appearance of NFT's and SP's in the visual regions of the occipital lobe correlates with deficits in visuospatial skills in the small subpopulation of AD patients with Balint's syndrome (14). Finally, it seems likely that the correlation between degree of cognitive impairment and the loss of synapses seen in AD reflects a loss of cortico-cortical projections (37). Thus, it appears that disruption of cortical connections can account for the type and severity of the clinical symptoms in AD. The second component of the disconnection/connectivity model is that the pattern of NFT's and SP's in the brains of patients with AD can be explained by the spread of pathological changes through interneuronal connections. One example that supports this concept is the analysis of hippocampal formation damage in AD. NFT's are observed in layer II neurons of the entorhinal cortex whose axons project to the molecular layer of dentate gyrus, an area frequently involved by SP's ( 16,17). SP's also accumulate in specific nuclei in the amygdala that receive hippocampal projections (19,24). NFT's accumulate in high-order association cortices ( 14,25,31), whose projections to other cortices terminate in regions affected with SP's. These observations are consistent with the hypothesis that SP's develop in the terminal zone of neurons that contain NFT's. Alternately, this data could be interpreted to imply that NFIs form in cells projecting to SP's. However, one can also find instances of areas severely affected by NFIs whose projection zone is not frequently affected by SP's. For example, subicular/CA 1 hippocampal neurons develop NF'Is. These neurons project strongly to layer IV of the entorhinal cortex which contains NFT's but little or no amyloid deposition (19). Other apparent discrepancies are found in an analysis of the visual system as described below. Thus, while it may be possible to predict which regions of the brain are affected at different stages of AD, it does not seem possible to predict the pattern of involvement of different brain regions based only on known anatomical connections.

Elemental and configural associations, the hippocampus and development

AbstractTwo views of the stimulus controlling learned behavior are contrasted. On the elemental view, the organism fractionates its environment into isolatable features or elements, and experience alters how it responds by strengthening or weakening associations among the elements. On the configural view, it is the representation of the pattern or conjunction of stimulus elements acting on the organism that acquires control over behavior. This paper addresses the issue of how to describe the stimulus from a comparative/organismic perspective and argues that separate neural systems are available that support both elemental and configural associations. Normal adult rats and rats with hippocampalformation damage, and different‐aged rats and children were compared on tasks that permit a solution based only on elemental associations and tasks that only can be solved if the organism can acquire configural associations. Subjects in all comparison conditions were able to solve tasks that permit an elemental solution, but animals with hippocampal‐formation damage, preweanling rats, and children less than 55 months of age were signficantly impaired on tasks that required solving configural associations. Some implications of this data pattern are discussed.

Damage to the hippocampal formation in rats selectively impairs the ability to learn cue relationships

We assessed the contribution of the hippocampal formation to performance in tasks that require rats to respond to a relationship between discriminative stimuli. The first experiment employed a nonmatching-to-sample procedure in a Y-maze. Three pairs of boxes were used which differed in brightness of the walls and in the odors that they contained. The rats were trained prior to receiving kainic acid and colchicine-induced damage to the hippocampal formation or electrolytic damage to the amygdala. After surgery all rats performed the nonmatching-to-sample task accurately if both brightness and odor cues were present in the sample and choice boxes or if the boxes contained either visual cues alone or odor cues alone. If the available cue modality was different in sample and choice boxes, then the amygdala-damaged, but not the hippocampal-damaged, rats performed accurately. In the second experiment control rats or rats with hippocampal formation damage were trained postoperatively in a conditional black/white discrimination task in a Y-maze. Only the control group successfully learned to select the white arm if the start box was illuminated and the black arm if the start box was dark. Subsequently, both groups learned a simple black/white discrimination. The same rats were tested in the hidden platform version of the Morris water task and only the control group learned to swim accurately to the goal. Both groups learned to swim accurately to a visible black platform. The results are consistent with the notion that the hippocampal formation is essential to learning that involves control exerted by a configural relationship among cues, independently of the spatial or conditional requirements of tasks.

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.

Configural association theory: The role of the hippocampal formation in learning, memory, and amnesia

It is proposed that the hippocampal formation makes a unique contribution to memory by providing the neural basis for the initial acquisition and storage of configural associations among events. A distinction is made between two kinds of memory processes: a simple associative process, which does not depend on the hippocampal formation, and a configural associative process, which does. The simple associative system records the organism’s experiences as changes in the strength of associations between elementary stimulus events. The configural associative system combines the representations of elementary stimulus events to construct unique representations and allows for the formation of associations between these configural representations and other elementary representations. In the present paper, the results of two experiments designed to test predictions of our theory are described. We then illustrate how the theory can be applied to explain a wide range of impairments that have been observed when learning and memory tasks have been employed to assess the effect of hippocampal formation damage. These include tasks that measure place learning, recognition memory, latent inhibition, serial-compound conditioning, discrimination-reversal learning, and stimulus-selection processes. The relationship of our position to some other views of hippocampal function is discussed, and we conclude with suggestions for future research.