Animal Model Of Human Amnesia Research Articles

Developing an animal model of human amnesia: The role of the hippocampus

This review summarizes a series of experiments aimed at answering the question whether the hippocampus in rats can serve as an animal model of amnesia. It is recognized that a comparison of the functions of the rat hippocampus with human hippocampus is difficult, because of differences in methodology, differences in complexity of life experiences, and differences in the degree of hippocampal damage. Notwithstanding, rats and humans with hippocampal damage are similarly impaired on analogous tasks that assess spatial memory, spatial pattern separation, spatial configural and arbitrary associations, temporal order memory, temporal pattern separation, sequential learning, and temporal associations. These data suggest that the rat can serve as a model of memory dysfunction (amnesia) as it relates to spatial and temporal processing of new information.

Long‐term spatial memory in rats with hippocampal lesions

In animal models of human amnesia, using lesion methods, it has been difficult to establish the role played by the hippocampus in the formation of long-term spatial knowledge. For example, lesions sustained after acquisition have generally produced a flat retrograde amnesia for spatial information. These results have not made it possible to dissociate the participation of the hippocampus in retrieval/performance processes from its participation in consolidation/retention. The present study was designed to investigate if electrolytic hippocampal lesions made before training lead to a deficit in the long-term retention of spatial knowledge when the rats show equal performance levels during the acquisition. Results show that lesioned rats learn a place response just as well as the control rats when, during the training, an intramaze cue orients the animal in its navigation towards the goal arm. One day after reaching criterion, lesioned and control rats remember the task perfectly during a transfer test in which the intramaze signal used previously is not present. However, 24 days later, the hippocampal animals manifest a profound deficit in the retention of the spatial information. When the spatial task learned during the acquisition phase requires only the use of a guidance strategy, control and lesioned animals show the same level of performance during the training phase and the same degree of retention during the retraining phase 24 days after criterion. Taken together, these results suggest that the hippocampus plays a crucial role in long-term retention of allocentric spatial information.

224 Mnestic block syndrome - neuroimaging and neuropsychological correlates

Relations between brain damage and memory disturbance are outlined with emphasis on the so-called amnesic syndrome. Following a brief introduction into forms of memory and memory failures, the basic causes of brain damage (with relevance to mnestic failures) are described. Thereafter, the two best-known forms of brain damage-amnesia relations are reviewed: the consequences of damage to medial temporal lobe structures and to diencephalic regions. For the cases with medial temporal lobe damage, evidence is reported in greater detail for H.M., who has been examined more than any other amnesic patient for more than 30 years now, as a considerable amount of literature has accumulated on his behavior in diverse situations.Other cases with more or less circumscribed damage to medial temporal lobe structures are reviewed so as to outline criteria for or against the hypothesis that there are regions within the medial temporal lobe whose damage might be critical for the amnesic syndrome.Two cases of diencephalic amnesia are summarized in particular (cases of Mair et al., 1979) as they have received extensive neuropsychological and neuropathological investigation. Other cases with, for example, Korsakoff's disease are reviewed, as well as cases with diencephalic, or combined mesencephalic-diencephalic damage without nutritional causes.A third group of patients with massive, but still selective amnesic disturbances are then described: cases of basal forebrain damage, followed by descriptions of Alzheimer's disease which has similarities in the underlying neuropathology. This leads over to cases with more generalized intellectual deteriorations (dementia), which may have developed on the basis of primarily cortical damage or damage principally to basal ganglia structures.After reviewing cases with mainly material-specific memory failures- usually as a consequence of restricted neocortical damage-a separate section follows on patients in whom retrograde amnesia is the prominent symptom.The contribution of animal models of human amnesia is critically reviewed and discrepancies are analyzed between human and animal memory disturbances. This section emphasizes the value of investigating inter-dependencies between brain structures by pointing out that relations between memory disturbances and brain damage may be more complicated than apparent from a simple structure-function assignment. This aspect is further followed up in the conclusions.

Pathogenesis of irradiation-induced cognitive dysfunction.

Neurocognitive dysfunction is a common sequela of cranial irradiation that is especially severe in young children. The underlying mechanisms of this disorder have not been described. The present review describes the role of the hippocampus and the anatomically related cortex in memory function and its marked susceptibility to ischemic and hypoxic injury. Based on studies of animal models of human amnesia and histopathological findings in the irradiated brain, the neurocognitive sequela of cranial irradiation can be seen to be mediated through vascular injury, resulting in ischemia and hypoxia in the hippocampal region. Recognition of the site and mechanisms of this injury may lead to the development of techniques to minimize the risks.

The animal model of human amnesia: long-term memory impaired and short-term memory intact.

Normal monkeys and monkeys with lesions of the hippocampal formation and adjacent cortex (the H+ lesion) were trained on the delayed nonmatching to sample (DNMS) task with a delay of 0.5 s between the sample and the choice. The animals with H+ lesions learned the task normally at this short delay and also exhibited the same pattern of response latencies as normal monkeys. This finding contrasts with previous observations that initial learning of the DNMS task with delays of 8-10 s is impaired after H+ lesions. The absence of an impairment at a delay of 0.5 s indicates that the H+ lesion does not affect short-term memory. In contrast, when monkeys with H+ lesions were tested at longer delays (> 30 s), an impairment was observed. This selective impairment occurred when the delays were presented sequentially (from 0.5 s to 10 min) and also when delays were presented in a mixed order (1 s, 1 min, and 10 min). The data indicate that the H+ lesion produces a selective impairment in long-term memory, in the absence of a detectable deficit in short-term memory or perception. Accordingly, the findings confirm the long-standing idea, based primarily on studies of humans, that short-term memory is independent of medial temporal lobe function. The findings thereby establish an important parallel between memory impairment in monkeys and humans and provide additional support for the validity of the animal model of human amnesia in the monkey.

Neuroanatomy of memory.

Three important developments have occurred in the area of during the past decade. The first was the recognition that there is more than one kind of (Cohen 1984; Schacter 1987; Squire 1982; Tulving 1985). Declarative (or, explicit memory) affords the capacity for con­ scious recollections about facts and events. This is the kind of that is usually referred to when the terms memory or remembering are used in ordinary language. Declarative can be contrasted with nondeclarative (or implicit) memory, a heterogeneous collection of nonconscious abilities that includes the learning of skills and habits, prim­ ing, and some forms of classical conditioning. In these cases, experience cumulates in behavioral change, but without affording access to any content. The distinction between declarative and nondeclarative is fundamental, because it has turned out that different kinds of are supported by different brain systems. The second important development was the establishment of an animal model of human amnesia in the monkey (Mahut & Moss 1984; Mishkin 1982; Squire & Zola-Morgan 1983). In the 1950s, Scoville & Milner (1957) described the severe amnesia that followed bilateral surgical removal of the medial temporal lobe (patient H.M.). This important case demon­ strated that is a distinct cerebral function, dissociable from other perceptual and cognitive abilities. Subsequently, surgical lesions of the medial temporai iobe in monkeys, which approximated the damage sus­ tained by patient H.M., were shown to reproduce many features of human impairment . In particular, both monkeys and humans were

Impairment of long-term memory and sparing of short-term memory in monkeys with medial temporal lobe lesions: a response to Ringo

During the last decade, an animal model of human amnesia was developed in the monkey. Studies using this model have identified structures in the medial temporal lobe that are essential for forming long-term memory (i.e. the hippocampus and the entorhinal, perirhinal and parahippocampal cortices). Recently, an important aspect of these studies was questioned by Ringo (Behav. Brain Res., 42 (1991) 123-134). He suggested that the data from the delayed non-matching-to-sample task, which has been extensively used in these studies, have been analyzed in a potentially misleading way. He reanalyzed the data from several laboratories by transforming percent correct data to a discriminability (d') measure based on signal detection theory. In monkeys with lesions, performance appeared to be equivalently impaired at short and long retention delays. He concluded that the data do not support the idea that medial temporal lobe damage produces an impairment in long-term memory, but not short-term memory. However, most of the studies he analyzed were not designed to address the distinction between short-term and long-term memory. We show here that, in studies designed to compare short-term and long-term memory directly, medial temporal lobe lesions impair long-term memory while leaving short-term memory intact. This result is obtained whether the data are analyzed using a percent correct measure, the d' measure, or an arcsine transform.

The Medial Temporal Lobe Memory System

Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.

Animal models of human amnesia and dementia: Hippocampal and amygdala ablation compared with serotonergic and cholinergic blockade in the rat

The behavioral effects of combined bilateral hippocampal and amygdala ablation (previously proposed as a model of human global amnesia) were compared to those seen with central blockade of the ascending cholinergic and serotonergic projections (a possible model of human global dementia) in male hooded rats. Rats were prepared with: (a) bilateral surgical lesions of the hippocampus and amygdala; (b) pharmacological blockade of central cholinergic and serotonergic function by systemic injections of scopolamine and p-chlorophenylalanine; and (c) neurotoxic lesions of the rostrally projecting serotonergic nuclei in the brainstem using intracerebral injections of 5,7-dihydroxytryptamine, later combined with scopolamine. The behavioral tests used were: an open field test, a swim-to-platform test, and a Lashley III maze. In all 3 tests, rats with either the neurotoxin lesions plus scopolamine or p-chlorophenylalanine plus scopolamine treatment showed greater impairments in comparison with controls than did the combined lesion group. These results indicate that simultaneous blockade of central serotonergic and cholinergic transmission has a greater effect on some aspects of the organization of behavior than large surgical lesions of the hippocampus and amygdala.

The Neuropsychology of Memory

Neuropsychology aims to describe how the brain accomplishes learning and memory, in a way that speaks both to cognitive psychology and neuroscience. This paper presents a summary of presently available information about the neuropsychology of human memory, emphasizing three ideas: a) The neural substrate of memory continues to change for a long time after initial learning. This change (memory consolidation) is distinct from the changes underlying forgetting and involves the medial temporal region of the brain. b) The nervous system honors the distinction between two kinds of learning and memory (procedural vs. declarative). The former is spared in amnesia and does not depend on the integrity of the particular brain regions that when damaged cause amnesia. c) Animal models of human amnesia in the monkey are now available. These models should permit those brain regions damaged in amnesia to be identified and should lead to more detailed neurobiological study of these regions.

The performance of amnesic subjects on tests of experimental amnesia in animals: delayed matching-to-sample and concurrent learning

A group of amnesic Korsakoff subjects and a group of alcoholic controls were trained on a test of visual recognition, delayed matching-to-sample with trial unique stimuli. This test was modelled on comparable tasks used in the development of animal models of human amnesia. It was found that the Korsakoff subjects were severely impaired when the task difficulty was increased by lengthening the retention delay beyond 10 sec or by increasing the number of items intervening between sample presentation and test. The amnesic subjects were also impaired on the acquisition of a set of concurrent visual discriminations. These results bear clear similarities to those obtained from experimental amnesic syndromes in monkeys.

Mechanisms of memory.

Recent studies of animals with complex nervous systems, including humans and other primates, have improved our understanding of how the brain accomplishes learning and memory. Major themes of recent work include the locus of memory storage, the taxonomy of memory, the distinction between declarative and procedural knowledge, and the question of how memory changes with time, that is, the concepts of forgetting and consolidation. An important recent advance is the development of an animal model of human amnesia in the monkey. The animal model, together with newly available neuropathological information from a well-studied human patient, has permitted the identification of brain structures and connections involved in memory functions.

Amnesia in monkeys after lesions of the mediodorsal nucleus of the thalamus.

Recent successes in developing an animal model of human amnesia in the monkey have made it feasible to try to identify with certainty the specific structures in the diencephalon and medial temporal region that cause amnesia when damaged. Monkeys with small lesions restricted largely to the posterior portion of the mediodorsal nucleus of the thalamus were given a test of memory sensitive to human amnesia and a second test that is analogous to the skill-based tasks performed normally by amnesic patients. The monkeys exhibited a marked impairment on the first test and performed normally on the second. The results show that circumscribed lesions of the mediodorsal nucleus can cause substantial amnesia.