Aging and spatial cognition.

The study of age-related changes in spatial behaviors has much in common with the study of age-related changes in classical conditioning. A comparison is made of research in these two areas, with the suggestion that future work in spatial behaviors pursue the same lines of investigation that have been effective in classical conditioning.

Within-subjects, parametric manipulations to investigate aging.

Parametric manipulation of experimental variables is important for both practical and theoretical reasons. Practically, age-related impairments in memory may be detected only at certain levels of difficulty. If the task is too simple, age-related cognitive impairments may not be sufficient to alter performance. If the task is too difficult, age-related cognitive impairments may not add significantly to the poor performance of younger controls. Thus, some intermediate level of difficulty is necessary to produce behavioral evidence on underlying age-related cognitive changes. Theoretically, parametric manipulations are important to identify the psychological processes responsible for the behavioral alterations. For example, consider the common finding of an age-related impairment in a delayed conditional discrimination task. If that impairment is produced by a primary deficit in recent memory, then the magnitude of the age-related impairment should increase with the length as the delay interval is increased, producing a statistical interaction between the age delay interval. Both the practical and theoretical considerations are illustrated with specific experiments, and have implications for the types of experimental design that can be most effective in demonstrating and explaining age-related changes in learning and memory.

Age-related spatial reference and working memory deficits assessed in the water maze.

Aged rats have spatial memory deficits relative to young rats. The extent of these deficits in intermediate-aged rats is not well established. The present study examined the pattern of age-related changes in spatial reference and working memory in four ages of Fischer-344 rats. Place discrimination (PD) in the Morris water maze measured spatial reference memory. Repeated acquisition (RA), a discrimination in which the escape platform location varied from session to session, measured spatial working memory. Fischer-344 rats, 4 months, 11 months, 17 months, and 24 months of age, were tested. Compared to 4-month-olds, 24-month-olds were significantly impaired on all six PD measures of performance, 17 months were significantly impaired on five PD measures, and 11 months were significantly impaired on only one PD measure. Only 24-month-olds had a significant working memory impairment in RA relative to 4 months. Reference and working memory measures were distinct as assessed by a principal components analysis. The results indicate a nonlinear age-related spatial memory decline in Fischer-344 rats from 4 to 24 months of age.

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats.

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Acetyl-1-carnitine. 1: Effects on mortality, pathology and sensory-motor performance in aging rats.

Three different test sites assessed the effects of acetyl-1-carnitine (AC) on age-related changes in general health, sensory-motor skills, learning, and memory. Two groups of rats began the experiments at 16 months of age. One group (OLD-AC) was given AC, 75 mg/kg/day, beginning at 16 months. The other group (OLD-CON) was treated identically except it was not given the drug. Beginning at 22 months of age, these rats and a group of young (3-4 months old) rats (YG-CON) were given a series of sensory-motor tasks. AC decreased mortality, and had no reliable effect on body weight, fluid intake, or the general health of the rats. These data indicate that a chronic dose of AC does not interfere with food and water intake, and may increase longevity. An age-related decline of performance occurred in most of the sensory-motor tasks; locomotor activity was reduced in a novel environment and in a runwheel, and the ability to prevent falling was reduced in tests on a taut wire, rotorod, inclined screen, and several types of elevated bridges. An age-related decline of performance did not occur in grooming, or in the latency to initiate several different behaviors. AC had no effect on performance in any sensory-motor task. These data indicate that the improvements produced by AC in some tests of spatial memory may be due to the effects of AC on cognitive abilities rather than on sensory-motor skills.

Acetyl-1-carnitine. 2: Effects on learning and memory performance of aged rats in simple and complex mazes.

Acetyl-1-carnitine (AC) was administered via drinking water for six months to one group (OLD-AC) of male F-344 rats beginning at 16 months of age, while another group (OLD-CON) of rats was given water only during that period. The rats were maintained on this treatment throughout behavioral testing, which began at 22 months of age. Performance of the OLD-AC and OLD-CON rats was compared to that of young control (YG-CON) rats on the following set of tasks: spontaneous alternation in the arms of a T-maze, two-choice simultaneous discrimination in the stem of a T-maze, rewarded alternation in the arms of a T-maze, spatial discrimination and reversal on a circular platform, spatial working memory in the radial 8-arm maze, long-term memory in the 14-unit T-maze, and for preference of the light or dark chamber of a two-compartment box. AC improved the long-term memory performance in the split-stem T-maze and on the circular platform but had no discernable effects on performance of aged rats in the other tasks. Possible reasons for the selectivity of this agent's action on behavior are suggested.

Individual differences in aging: behavioral and neurobiological correlates.

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

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.

Attention and the frontal cortex as examined by simultaneous temporal processing.

The brain mechanisms involved in attention and memory were examined by testing rats in temporal discriminations designed to emphasize these cognitive processes. Normal rats were able to time each of two stimuli whether they were presented alone or together. Rats with lesions of the frontal cortex (FC) or nucleus basalis magnocellularis (NBM) were able to time each stimulus when it was presented alone, but not when it was presented together with another stimulus. Rather, these rats timed only the intruding stimulus and ignored the other, demonstrating a failure of divided attention. Rats with lesions of the fimbria-fornix (FF) or medial septal area (MSA) performed the divided attention task normally, but failed to remember the duration of a stimulus that had been terminated temporarily earlier in the trial, demonstrating a failure of working memory. These results provide another informative dissociation between the functions of the frontal and hippocampal systems, emphasizing frontal involvement in attention, and hippocampal involvement in working memory.

Neurons in the lateral agranular frontal cortex have divided attention correlates in a simultaneous temporal processing task.

The frontal cortex is an important brain area for divided attention. Lesions of the lateral agranular frontal cortex in rats disrupt divided attention in a simultaneous temporal processing task. In the present study, the activity of lateral agranular neurons was examined while rats performed a simultaneous temporal processing procedure. Rats were trained to time two stimuli (a light and a tone), each associated with a different fixed interval. Simple trials, in which a single stimulus was presented, and compound trials, in which both stimuli were presented simultaneously, occurred randomly in a session. Rats were able to divide attention between the two stimuli, as assessed by the pattern of lever presses. Approximately 50% of lateral agranular neurons responded to at least one phase of the task with four response patterns observed. The activity of type 1 cells (60%) was altered to compound, but not simple, stimuli. Type 2 cells (10%) responded to both types of simple stimuli and to compound stimuli. Type 3 cells (27%) had changes in firing rate to one type of simple stimulus and to compound stimuli. Type 4 cells (3%) responded to one type of simple stimulus, but were unresponsive to all other stimuli. The large proportion of type 1 cells supports the hypothesis that the lateral agranular cortex is important in divided attention. Previous studies have suggested that the lateral agranular cortex in rats is equivalent to the primary motor cortex. If so, the results from the present study provide evidence that the lateral agranular cortex may have some cognitive functions, in addition to being part of the motor system.

Intrahippocampal grafts of fetal basal forebrain tissue alter place fields in the hippocampus of rats with fimbria-fornix lesions.

Intrahippocampal grafts of fetal basal forebrain tissue have been shown to restore several aspects of neural function, including some degree of behavioral recovery in spatial memory tasks, in rats with fimbria-fornix lesions. Place fields, the behavioral correlates of complex-spike unit activity recorded in the hippocampus of rats, are altered by fimbria-fornix lesions, and provide an important measure of the functioning circuitry of the hippocampus after grafts. To investigate the effects of grafts on hippocampal circuitry, complex-spike units were recorded while the rats traversed a radial maze. Quantitative analyses of spatial activity showed that units in normal rats had spatially clustered, reliable place fields that were stable despite alterations of the maze. In contrast, units in rats with fimbria-fornix lesions had more dispersed, less reliable place fields that were disrupted when the maze was covered or rotated. Compared to rats with fimbria-fornix lesions, rats with grafts and units with more tightly clustered, more reliable, and more stable place fields when the maze was altered. The results suggest that: (1) fimbria-fornix lesions disrupt some aspects of complex-spike place field activity; (2) the functioning of hippocampal circuitry is influenced by fetal basal forebrain grafts; and (3) the grafts may ameliorate the effects of lesions on spatial behaviors by influencing critical aspects of place field activity in the hippocampus.

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.

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.

Hippocampal and amygdaloid involvement in working memory for nonspatial stimuli.

Hippocampal lesions in rats lead to an impairment of performance in spatial delayed conditional discriminations. The effect of such lesions on nonspatial tasks is controversial. In monkeys, both the hippocampus and the amygdala are involved in nonspatial delayed conditional discriminations. The effect of amygdaloid lesions in rats on this type of task has not been studied. To clarify the role of hippocampus and amygdala in a cue-relevant/space-irrelevant delayed conditional discrimination, rats were trained on a delayed match-to-sample task with visual and tactile cues as discriminative stimuli. Rats were then given one of five lesions: control, complete fimbria-fornix, partial fimbria-fornix, complete amygdala, or partial amygdala. Amygdaloid lesions, partial or complete, did not impair choice accuracy. Fimbria-fornix lesions did impair choice accuracy, and the magnitude and duration of the impairment was a function of the size of the lesion. Partial fimbria-fornix lesions produced a slight impairment that disappeared with continued testing. Complete fimbria-fornix lesions produced chance performance throughout postoperative testing. These results indicate that the fimbria-fornix, but not the amygdala, is involved in nonspatial delayed match-to-sample.

Fimbria-fornix lesions impair spatial working memory but not cognitive mapping.

Three experiments were designed to evaluate the relative merits of two theories of hippocampal function, the cognitive mapping theory and the working memory theory. Rats were tested in a series of maze tasks that varied in memory requirements. In the experiments that required cognitive mapping but not working memory (Experiments 1 and 3), rats with fimbria-fornix lesions reached stable levels of performance that were as accurate as those of control rats, and they also performed accurately during transfer tests, results demonstrating that they used a cognitive mapping strategy to solve the discrimination. In the experiment that required working memory (Experiment 2), rats with fimbria-fornix lesions performed at chance levels during all of postoperative testing, and they distributed their choices randomly between the correct and the incorrect goals. These results are seen as generally refuting the predictions made by the cognitive mapping theory and supporting the predictions made by the working memory theory. Additional analyses (Experiment 3) examined the nature of a transitory impairment exhibited by rats with fimbria-fornix lesions in two tasks that did not require working memory. Postoperatively, the performance of the rats with lesions was initially impaired but recovered to normal levels with a time course similar to that seen during preoperative acquisition. These results are seen as requiring an extension of the working memory theory of hippocampal function, and discussion is focused on the possibility of a temporary retrograde amnesia following fimbria-fornix lesions and the distinctions between different types of memory abilities.

Hippocampal and amygdaloid involvement in nonspatial and spatial working memory in rats: effects of delay and interference.

Parametric manipulations of the task demand were used to examine the role of the hippocampus and amygdala in nonspatial and spatial working memory in rats. Hippocampal lesions produced an immediate and long-lasting impairment of nonspatial working memory in an operant task. The memory deficits increased as the delay interval and the amount of proactive interference increased. Hippocampal lesions severely impaired spatial working memory in spatial alternation. Extensive postoperative testing reduced the magnitude of impairment of nonspatial but not spatial working memory. Amygdaloid lesions did not impair any aspect of performance in 2 tasks. The results suggest that the hippocampus, but not the amygdala, is involved in working memory and the task demand is a critical determinant for observing impairments of nonspatial working memory following hippocampal lesions.

Nucleus basalis magnocellularis and attention: effects of muscimol infusions.

The basal forebrain is important in cognitive processing. Most studies have focused on the importance of this area in mnemonic processing. However, the nucleus basalis magnocellularis (NBM), which is a major component of the basal forebrain, may also be involved in attentional processes. Attention can influence the sensitivity of perceptual processes, as assessed by discriminability, or the selection of response strategies, as assessed by bias. This experiment examined whether temporary inactivation of the NBM, using the GABA agonist muscimol, would interfere with attention. Each rat was tested in a 2-choice reaction time (RT) task in which stimulus frequency was varied. RT and error rate increased, and discriminability decreased following muscimol infusions into the NBM. Bias was unchanged. The pattern of results provides evidence that the NBM is important in attention, and this influence of the NBM acts primarily on perceptual aspects of attention.

Mnemonic theories of hippocampal function.

Although mnemonic interpretations of hippocampal function in people have been readily accepted for many years, similar interpretations of hippocampal function in animals have received a number of challenges. This article reviews two of these challenges, shows how they were resolved in favor of some kind of mnemonic interpretation, and then suggests ways in which these types of interpretations must change in order to encompass new data.

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.

Basal forebrain lesions and memory: alterations in neurotensin, not acetylcholine, may cause amnesia.

Behavioral impairments produced by lesions of the nucleus basalis magnocellularis (NBM) are usually attributed to the loss of cholinergic cells. A comparison between the effects of 2 different neurotoxins, ibotenic (IBO) and quisqualic (QUIS) acid, reveals that this interpretation is inconsistent with the data. Rats were given injections of either IBO or QUIS into the NBM and tested on an alternation task in a T-maze. At the start of behavioral testing, both IBO and QUIS rats had impaired choice accuracy. At the end of behavioral testing, however, IBO rats, but not QUIS rats, were more impaired than controls, and IBO rats were more impaired than QUIS rats. IBO decreased choline acetyltransferase (ChAT) activity and [3H] neurotensin binding in the neocortex. QUIS decreased ChAT activity but did not change [3H] neurotensin binding. The cholinergic system may not be the critical component responsible for behavioral impairments following NBM lesions.