Biomedical subjects

D S Olton

Publications and source records attributed to D S Olton.

At least 19 recordsLinked to original sources

PubMed1992

Galanin in the medial septal area impairs working memory.

Galanin, a peptide of 29 amino acids, is co-localized with acetylcholine in a subpopulation of neurons of the medial septal area (MSA) that project to the hippocampus. Galanin reverses the actions of acetylcholine in several biochemical and behavioral procedures, and may be involved in memory processes. To test the possibility that galanin acts on the cell bodies of MSA neurons, two measures of septohippocampal function were assessed following intra-septal microinfusion of galanin or two synthetic fragments of galanin (1-16 and 21-29). The behavioral measure was choice accuracy in a working memory task in a T-maze. The electrophysiological measure was hippocampal theta activity recorded from the dentate hilus. The galanin fragment, 1-16, and the complete peptide, 1-29, decreased choice accuracy and decreased hippocampal theta activity in a dose-dependent fashion. Saline and the 21-29 fragment had no effect on choice accuracy and hippocampal theta. Sensorimotor performance was unaffected. These findings demonstrate that galanin impairs working memory when administered directly into the MSA and suggest that galanin inhibits MSA neural activity.

Animals↗

PubMed1992

Tolman's cognitive analyses: predecessors of current approaches in psychology.

Hindsight is always helpful. I hope that I have provided some appreciation of why the experiment by Tolman et al. (1946) is a classic and deserves to be included in this series. Evaluating the extent to which this particular experiment actually influenced the development of all of the endeavors described above is difficult, and I leave it to those individuals who have an interest in the history of science to draw the appropriate conclusions. Even without direct causality, the continued relevance of this experiment is striking. We might all wish that we have sufficient foresight to investigate significant problems in such a way that our own contributions are still considered important almost 50 years after we make them.

Animals↗

PubMed1992

Hippocampus, fimbria-fornix, amygdala, and memory: object discriminations in rats.

Rats with lesions of the fimbria-fornix, hippocampus, or hippocampus and amygdala were tested in object discriminations commonly used with monkeys. Two 1-pair object discriminations were learned preoperatively and tested postoperatively. Additional postoperative testing included acquisition of a third 1-pair object discrimination, an 8-pair concurrent object discrimination, and spatial alternation. All lesions impaired performance in the 8-pair object discrimination and in spatial alternation but not in the 1-pair object discriminations. Data from this study and from previous studies indicate that the hippocampus in both rats and monkeys has an important role in the mnemonic processes required for concurrent object discriminations and that variations of the procedure for concurrent object discriminations can be an effective tool for investigating hippocampal function.

Amygdala↗

PubMed1992

Expectancy and stimulus frequency: a comparative analysis in rats and humans.

We examined whether expectancy, one of several factors influencing attention, is similarly affected in rats and humans by manipulation of relative stimulus frequency. A two-choice reaction time (RT) task was developed for rats, and an analogous task was used for humans. Errors, RTs, discriminability, and response bias were measured. Both rats and humans shifted their response bias to the more frequent stimulus, with no change in overall discriminability. As stimulus probability or stimulus repetition increased, RTs and errors decreased. These results illustrate the similarity of expectancy in rats and humans. This two-choice RT task for rats can be used in future studies to examine the neuronal mechanisms of expectancy and attention.

Animals↗

PubMed1991

Individual differences in aging: behavioral and neural analyses.

Aged populations have remarkable variability in recent memory and cognitive mapping. Although some individuals may have substantial age-related impairments, others perform almost as well as young individuals. This paper reviews the relevant data on aged rats and indicates two challenges for biomarkers of aging. The first is to provide an appropriate quantitative description of these individual differences. The second is to use them effectively as markers for age-related changes in psychological functions and their neural substrates.

Aging↗

PubMed1990

Nucleus basalis magnocellularis and memory: differential effects of two neurotoxins.

Although the cholinergic system is involved in memory, noncholinergic systems may also contribute to memory. Lesions of the nucleus basalis magnocellularis (NBM) produce behavioral impairments and reduction of cholinergic markers in the frontal cortex (FC). The present study compared the behavioral effects of lesions made with two different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid. IBO or QUIS was injected into the NBM, and rats were tested in three different tasks: cued delayed nonmatch-to-sample (CDNMS), spatial delayed nonmatch-to-sample (SDNMS), and spatial two-choice simultaneous discrimination (STCSD). IBO producted a greater behavioral impairment than QUIS in the CDNMS and the SDNMS, although QUIS produced a greater drop in choline acetyltransferase (ChAT) activity in the cortex than IBO. At the end of behavioral testing, IBO rats, but not QUIS rats, were impaired in the retention of both tasks. The fact that QUIS lesions produced a greater loss of NBM cholinergic neurons, as determined by decreased ChAT activity, but less of a behavioral impairment in both a spatial and nonspatial task, suggests that the loss of noncholinergic NBM neurons must contribute to the memory impairments following NBM cell loss.

Animals↗

PubMed1990

Dementia: animal models of the cognitive impairments following damage to the basal forebrain cholinergic system.

The finding that patients with Alzheimer's disease (AD) have significant degeneration of neurons in the basal forebrain cholinergic system (BFCS) stimulated a great deal of research to determine the cognitive impairments resulting from selective damage to this area. The experiments reviewed here indicate that lesions of the nucleus basalis magnocellularis (NBM) and of the medial septal area (MSA) reproduce the behavioral symptoms following lesions of their respective target sites, the frontal cortex (FC) and the hippocampus (HIP). Impairments of recent memory are one of the most striking symptoms in AD patients at the beginning of their disease, and lesions of the BFCS induce similar impairments. Comparisons of the effects of the lesions produced by different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid, have raised questions about the role of cholinergic and noncholinergic neurotransmitter systems in the basal forebrain. The implications of these data for the cholinergic hypothesis of mnemonic functions are discussed.

Animals↗

PubMed1990

Cholinergic and GABAergic modulation of medial septal area: effect on working memory.

The role of the septohippocampal pathway in working memory was investigated by direct microinfusion of compounds into the medial septal area (MSA). Behavior was measured by performance in a continuous spatial alteration task in a T maze, and hippocampal theta rhythm was also recorded. Intraseptal saline had no effect on choice accuracy or hippocampal theta rhythm. Tetracaine decreased choice accuracy and theta rhythm 10 min, but not 90 min, after infusion. Likewise, muscimol and scopolamine produced a transient, dose-dependent suppression of hippocampal theta rhythm and a simultaneous dose-dependent impairment in choice accuracy. A significant correlation (r = .78) emerged between a compound's influence on theta rhythm and its effect on choice accuracy. The data support a role for the septohippocampal projection in working memory and suggest that gamma-aminobutyric acid and acetylcholine may have opposing influences on neurons in the MSA.

Acetylcholine↗

PubMed1990

The development of behavioral tests to assess the effects of cognitive enhancers.

The search for drugs that enhance cognition requires the development of behavioral tests for animals. These tests must be able to identify potentially therapeutic drugs and reject ineffective drugs. A reference compound for cognitive enhancement does not exist, and may not be a reasonable goal. Therefore, a coherent conceptual and experimental framework is needed to organize the various research endeavors in this area. This paper proposes a framework to assist in the development and evaluation of specific behavioral tests. It requires explicit identification of the goals of the research, the cognitive process, the neural systems involved in the process, the selectivity and sensitivity of tasks that measure the process, the validity of the behavioral tasks as a model to predict the effects of the drug in humans.

Alzheimer Disease↗

PubMed1990

Behavioral models of memory and amnesia.

In modelling memory and amnesia, the different forms of cognition must be distinguished. For memory, distinctions between acquisition, storage, and retrieval must be made and the different kinds of memory (e.g., immediate, working, reference) identified. Other notions, such as attention, orientation, and vigilance also belong under the heading "cognition". Thus the term "cognition enhancer" is imprecise because it does not indicate which kind of cognition is to be enhanced. Animal models should be developed for each type of cognition, be based on information from the clinic, and attempt to be specific. Examples of models more specific than the passive avoidance test were discussed and included the radial maze, in which different kinds of memory could be analyzed and correlated with, for example, changes in central cholinergic activity. From the point of view of drug development an important distinction was made between "empirical" and "simulation" models. In other areas of psychopharmacology "empirical" models have been widely used because they show predictable responses to known reference compounds. In the field of cognition there are no generally recognized reference compounds and therefore no "empirical" models. There is therefore a need for "simulation" models which imitate the various aspects of cognition and its pathology. The major criterion for validating this kind of model is that it should show changes similar to those observed in humans either resulting from a particular pathology or from a particular drug treatment.

Amnesia↗

PubMed1990

Poor blood glucose regulation predicts sleep and memory deficits in normal aged rats.

Poor glucose regulation predicts memory deficits in individual elderly humans. The present experiment determined whether glucose regulation was also related to memory and to sleep in aged rodents. Glucose regulation, inhibitory avoidance, and daytime sleep were assessed in young (3-month-old) and old (24-month-old) rats. Correlations were obtained between glucose regulation and the other variables in individual rats. In old rats, the magnitude of increases in blood glucose levels after glucose injections (500 mg/kg) was inversely correlated with retention of inhibitory avoidance and duration of paradoxical sleep bouts. In young rats, these measures were not significantly correlated. Because the deficits in sleep and memory in aged rats were largely confined to those rats with poor glucose control, peripheral glucose regulation may be a useful biological marker that accompanies cognitive and neurobiological dysfunction during aging.

Aging↗

PubMed1990

Electrophysiological correlates of recovery of function.

The present experiment was designed to determine the extent to which two different mechanisms were responsible for the recovery of function produced by grafts of fetal basal forebrain tissue into the hippocampus of rats given fimbria-fornix lesions. The place fields of single units in the hippocampus were recorded as rats moved about a radial arm maze. Two measures of the discriminative stimuli identifying the place fields were determined: place stability, maze stability. In control (CON) rats, place stability was high and maze stability was low, indicating that the relevant discriminative stimuli were extra-maze cues. In rats with fimbria-fornix (FF) lesions, place stability was low and maze stability was high, indicating that the relevant discriminative stimuli came from the maze itself. In rats given grafts of fetal basal forebrain tissue (GRAFT), place stability was increased and maze stability was reduced as compared to FF rats. These results indicate that the grafts produced recovery of function through restoration of normal hippocampal unit activity, rather than by reorganization of new neural networks.

Animals↗

PubMed1990

Long-term effects of cholinergic agonists on memory.

Animal models provide important information about strategies that can be used to assess the effects of chronic exposure to drugs or other compounds. Furthermore, when used in conjunction with analyses designed to utilize the many advantages of animal models to examine learning and memory, these kinds of experiments can have significant ramifications for assessing the mnemonic effects of chronic drug use in people. Finally, given that aging is accompanied by significant deterioration of neurochemical systems, which may compromise the functions of those systems, the results from the experiments with DFP predict that changes in learning and memory abilities that are not apparent in young individuals may begin to surface as those individuals age or may appear following any other kind of insult to their nervous system.

Animals↗

PubMed1990

Dietary acetyl-L-carnitine improves spatial behaviour of old rats.

Acetyl-L-carnitine was given to aging rats to determine the extent to which it changed age-related impairments in several different behaviours. One group of rats was given acetyl-L-carnitine, 80 mg/day, beginning at 16 months of age. A second group of rats was housed and treated identically, except that no drug was administered. At 22 months of age, both groups of rats began a series of behavioural tests, along with a group of young rats, four months of age. The tests included: place learning on a circular platform, probe reversal of place learning on a circular platform, two choice simultaneous spatial discrimination in the stem of a T-maze spatial alternation in the arms of a T-maze, and sensory-motor behaviour (initiation of walking, turning in an alley, walking on a square, round, and rectangular bridge, turning on an inclined grid, holding on to a wire, light-dark preference). The tasks varied in their sensitivity to age-related impairments. These data indicate that long-term therapy with acetyl-L-carnitine attenuates certain age-related cognitive deficits and may have a beneficial effect on longevity.

Acetylcarnitine↗

PubMed1989

Effects of fornix transection and cingulate cortical ablation on spatial memory in rhesus monkeys.

This study, together with a parallel study in rats (Markowska et al. 1988), attempted to relate the effects of hippocampal-system damage on similar tasks in both rats and monkeys. Not only were monkeys given a task (Experiment 1) which was of the sort usually used with rats, but in the companion study rats were given tasks (Experiment 2) like those usually used with monkeys. Experiment 1 examined the performance of rhesus monkeys with hippocampal-system damage on a spatial working memory task. Monkeys were trained preoperatively on delayed nonmatching-to-sample in a T-maze, placed into groups matched for their preoperative learning scores, and then received one of three treatments: 1) transection of the fornix; 2) ablation of the cingulate cortex; or 3) a sham operation. Monkeys with fornix transection were severely and significantly impaired, but monkeys with cingulate cortical ablations were not significantly impaired, relative to the controls. The results demonstrate that monkeys with fornix transection are severely impaired on a spatial working memory task requiring locomotion and, taken together with earlier work, suggest that the effect of fornix transection in both rodents and nonhuman primates is at least qualitatively similar (see Markowska et al. 1988). Experiment 2 assessed the role of the fornix and cingulate cortex in three conditional tasks in which the monkeys were provided with various spatial cues to indicate which one of two objects was rewarded. Both experimental groups were unimpaired, relative to the control group, on all three tasks, indicating that fornix transection does not produce a general impairment in place learning.

Animals↗

PubMed1989

A comparative analysis of the role of fornix and cingulate cortex in memory: rats.

In order to compare the role of the fornix (FX) and cingulate cortex (CC) in memory, rats were trained in a series of discriminations using procedures that were the same as those used for monkeys (Murray et al. 1986, 1988). A spatial delayed nonmatching-to-sample (DNMS) discrimination tested recent memory for spatial location in a T maze using interrun intervals (IRI) that varied from 5 s to 15 min. FX and CC lesions produced a substantial impairment in the performance of this task during postoperative testing. Three conditional discriminations (CD) followed. In each one, the rat was presented with two objects, only one of which was correct. The nature of the conditional stimuli changed in each discrimination: the place of the maze in the room; the direction that the rat moved to approach the objects; the side (left or right) to which the rat turned. Control rats learned all three types of conditional discriminations. FX and CC lesions did not impair choice accuracy. In a subsequent repetition of the spatial DNMS procedure, FX and CC lesions again produced a substantial impairment, indicating that the lack of an impairment in the three CDs was not due to recovery of function. These data indicate that the hippocampal system and its connections through the fornix are importantly involved in spatial working memory in both rats and monkeys, and that the CDs do not require this type of memory. The results are discussed in the context of different theories of the brain mechanisms involved in memory.

Animals↗

PubMed1989

Frontal cortex, timing and memory.

Two sets of experiments examine the psychological functions and neural organization of the frontal lobes. The first set investigates the effects of lesions of the frontal cortex (FC) on the ability to perform temporal discriminations, using the techniques and theoretical framework of scalar timing theory. FC lesions changed the reference memory for the expected time of reinforcement, so that rats expected reinforcement later than it actually occurred. These results demonstrate that the FC modulates temporal memory. The second set of experiments examined the behavioral effects of lesions in the nucleus basalis magnocellularis (NBM), an area in the basal forebrain that has a significant projection to the frontal cortex. NBM lesions produced impairments in many different tasks assessing both recent and long-term memory. A comparison of the behavioral and neurochemical effects of different types of lesions in the NBM examines the role of cholinergic and noncholinergic neurotransmitters in these behavioral deficits. These data demonstrate that a "frontal syndrome" can follow selective lesions in the NBM, and indicate that the NBM must have a strong role in frontal lobe function.

Animals↗

PubMed1989

Cognitive enhancers: potential strategies and experimental results.

1. Cognitive impairments follow natural processes such as aging, diseases, exposure to neurotoxins, and traumatic injury. In all of these instances, the brain possesses some capability for recovery. 2. A cognitive enhancer is any compound that will help this recovery occur more rapidly, or increase the final level of performance. 3. This chapter describes the types of strategies that can be used to develop a cognitive enhancer with emphasis on studies of the cholinergic system.

Animals↗