Age-related changes in working and reference memory performance and locomotor activity in the Wistar rat

Wistar rats of three age groups were tested in an automated tunnel-maze system of variable geometry to investigate whether changes in spontaneous locomotor activity and in learning and memory develop differentially or in a correlated fashion as a function of age. Senescent (30 months) as well as mature-adult (17 months) rats showed an age-correlated decline of locomotor activity as compared to the mature-young (5 months) group. Both working-memory (measured as within-trial arm discrimination performance) and reference-memory (measured as avoidance of "blind alley" visits) were severely affected in the senescent group, whereas the middle-aged animals suffered only from a working-memory deficit. The findings provide evidence that locomotor deficits do not necessarily interfere in the assessment of age-related changes in cognitive performance. Furthermore the results support the hypothesis that working and reference memory have different underlying physiological correlates and that these neuronal systems are differentially affected by the aging process.     

Spatial Working Memory in Aging and Mild Cognitive Impairment: Effects of Task Load and Contextual Cueing

ABSTRACT

Mild Cognitive Impairment (MCI) is characterized by episodic memory deficits, while aspects of working memory may also be implicated, but studies into this latter domain are scarce and results are inconclusive. Using a computerized search paradigm, this study compares 25 young adults, 25 typically aging older adults and 15 amnestic MCI patients as to their working-memory capacities for object-location information and potential differential effects of memory load and additional context cues. An age-related deficit in visuospatial working-memory maintenance was found that became more pronounced with increasing task demands. The MCI group additionally showed reduced maintenance of bound information, i.e., object-location associations, again especially at elevated memory load. No effects of contextual cueing were found. The current findings indicate that working memory should be considered when screening patients for suspected MCI and monitoring its progression.     

Effects of Unilateral Entorhinal Cortex Lesion on Retention of Water Maze Performance

In a previous study, adult male Sprague-Dawley rats with unilateral, electrolytic entorhinal cortex lesions showed significant deficits in acquisition of a water maze task that measured working memory. The 10 days of testing used two trials per day with an intertrial interval of 1 h, and the rats with entorhinal damage were impaired in total distance to the platform in both trials. In the present retention study, rats who learned the same task prior to injury and were then retested for 5 days after lesion showed only a first day deficit in total distance to platform in the second trial. Analysis of swim patterns indicated that rats with unilateral entorhinal lesions used an altered strategy in retention testing to find the platform in the second trial of each day and incorporated the use of headings appropriate for Trial 1 only. This altered or compensatory strategy was not the optimum choice for problem solution. Although the rats then were able to switch headings and find the platform without significant impairment in total distance to platform on days 2–5 of testing, the use of an initial incorrect strategy indicated subtle residual deficits in cue integration and use of working memory.     

Glucose treatment reduces memory deficits in young adult rats fed high-fat diets

Feeding rats high-fat diets for 3 months produces a widespread cognitive deficit that affects performance on a wide range of learning and memory tasks. The present study tested the hypothesis that this effect is related to a fat-induced impairment in glucose metabolism. Following 3 months of dietary intervention (20% by weight fat diets, composed primarily of either beef tallow or soybean oil versus standard laboratory chow), male Long-Evans rats were tested on a variable interval delayed alternation (VIDA) task that measures learning and memory functions that differentially involve specific brain regions. Relative to rats fed chow, rats consuming the high-fat diets were impaired on all aspects of VIDA performance. Following baseline testing, rats were maintained on their respective diets and the effect of glucose administration (100 mg/kg BW; i.p.) was examined. For the next 6 days, animals alternately received injections of saline or glucose 30 min prior to VIDA testing. Glucose treatment improved performance, with the effect being most pronounced at the longer intertrial intervals where task performance is sensitive to hippocampal impairment. Importantly, the beneficial effect of glucose were confined to those animals consuming the high-fat diets and were not observed in rats fed chow. These results demonstrate that glucose administration can overcome those deficits associated with hippocampal function in rats fed high-fat diets and are consistent with the hypothesis that high-fat diets, in part, mediate their effect through the development of insulin resistance and glucose intolerance.     

The effects of attention on age-related relational memory deficits: evidence from a novel attentional manipulation

Healthy aging is often accompanied by episodic memory decline. Prior studies have consistently demonstrated that older adults show disproportionate deficits in relational memory (RM) relative to item memory (IM). Despite rich evidence of an age-related RM deficit, the source of this deficit remains unspecified. One of the most widely investigated factors of age-related RM impairment is a reduction in attentional resources. However, no prior studies have demonstrated that reduced attentional resources are the critical source of age-related RM deficits. Here, we used qualitatively different attention tasks and tested whether reduced attention for relational processing underlies the RM deficit observed in aging. In Experiment 1, we imposed either item-detection or relation-detection attention tasks on young adults during episodic memory encoding and found that only the concurrent attention task that involves relational processing disproportionately impaired RM performance in young adults. Moreover, by ruling out the possible confound of task difficulty on the disproportionate RM impairment, we further demonstrated that reduced relational attention is a key factor for the age-related RM deficit. In Experiment 2, we replicated the results from Experiment 1 by using different materials of stimuli and found that the effect of relational attention on RM is material general. The results of Experiment 2 also showed that reducing attentional resources for relational processing in young adults strikingly equated their RM performance to that of older adults. Thus, this study documents the first evidence that reduced attentional resources for relational processing are a critical factor for the relational memory impairment observed in aging.     

Effects of Unilateral Entorhinal Cortex Lesion and Ganglioside GM1 Treatment on Performance in a Novel Water Maze Task

Transient deficits have been reported after unilateral entorhinal cortex (EC) lesion. To determine whether there is a more persistent deficit, adult male Sprague–Dawley rats with electrolytic or sham lesions of the left entorhinal cortex were examined on acquisition of a modified working memory task in the Morris water maze. This delayed matching-to-sample task, with a 1-h intertrial interval, reveals a significant deficit in total distance to platform in both presentation (Trial 1) and matching (Trial 2) in the rats with entorhinal lesions. We have also found that this test can be used to assess significant deficits in perseveration (repeated nonproductive movement) in rats with entorhinal lesions. The deficits can be seen up to 16 days postinjury. Administration of ganglioside GM1 resulted in a moderate improvement in performance in both water maze measures analyzed. All groups (sham operated, lesion with saline treatment, and lesion with ganglioside GM1 treatment) were given three other tests, which were used to evaluate possible contributing factors to deficient water maze performance. A one-trial test for exploration of novel objects revealed no significant, simple working memory deficit in any group. Plus maze testing, to assess possible differences in levels of anxiety or increased activity as a component of water maze performance, also revealed no differences in the three groups. All groups were also similar in motor activity, shown by monitoring of activity levels. The worsened water maze performance observed in rats with EC lesion may be related to deficits in working memory ability within the framework of acquisition of a more complex spatial learning task.     

Amygdala and "emotional" modulation of the relative use of multiple memory systems

The basolateral amygdala modulates the cognitive and habit memory processes mediated by the hippocampus and caudate nucleus, respectively. The present experiments used a plus-maze task that can be acquired using either hippocampus-dependent "place" learning or caudate-dependent "response" learning to examine whether peripheral or intra-basolateral amygdala injection of anxiogenic drugs would bias rats towards the use of a particular memory system. In Experiment 1, adult male Long-Evans rats were trained to swim from the same start point to an escape platform located in a consistent goal arm, and received pre-training peripheral injections of the alpha(2)-adrenoceptor antagonists yohimbine (2.5 or 5.0 mg/kg), RS 79948-197 (0.05, 0.1, or 0.2 mg/kg), or vehicle. On a drug-free probe trial from a novel start point administered 24h following acquisition, vehicle treated rats predominantly displayed hippocampus-dependent place learning, whereas rats previously treated with yohimbine (2.5, 5.0 mg/kg) or RS 79948-197 (0.1 mg/kg) predominantly displayed caudate-dependent response learning. In Experiment 2, rats receiving pre-training intra-basolateral amygdala infusions of RS 79948-197 (0.1 microg/0.5 microl) also predominantly displayed response learning on a drug-free probe trial. The findings indicate (1) peripheral injections of anxiogenic drugs can influence the relative use of multiple memory systems in a manner that favors caudate-dependent habit learning over hippocampus-dependent cognitive learning, and (2) intra-basolateral amygdala infusion of anxiogenic drugs is sufficient to produce this modulatory influence of emotional state on the use of multiple memory systems.     

Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats

Sprague-Dawley rats were used to study the effects of ibotenic acid lesions of the anterior (A.Th.) and the dorsomedial (MD) thalamic nuclei on learning and memory. Memory was assessed by employing a temporal alternation task in a straight alley with varying intertrial intervals. In addition, spatial orientation and response flexibility were evaluated on a radial maze and on a spatial reversal task (SSDR). The results indicated that MD rats required more trials to learn the temporal alternation task and exhibited impaired performance compared to A.Th. and control groups at the shortest delay (15 s). In contrast, compared to the control group, A.Th. subjects which required less trials to master the task and exhibited normal performance at the 15-s delay were impaired when the intertrial interval was increased to 45 s. Whatever the lesion, no impairments were found in the SSDR or the radial maze while only MD lesions were found to result in a night hyperactivity associated with greater food and water consumptions. These findings indicate that A.Th. and MD are differentially involved in learning and memory processes. It is suggested that the MD is mostly involved in registering new information while the A.Th. plays a role in the maintenance of information over time.     

Effects of increased processing demands on age differences in working memory

Three studies investigated (a) the plausibility of the claim that increasing the processing demands in a memory task contributes to greater involvement of a central processor and (b) the effects of altering reliance on the central processor on the magnitude of age-related differences in working-memory tasks. In the first study, young adults performed versions of 2 tasks presumed to vary in the degree of reliance on the central processor. In the second and third studies, young and older adults performed versions of a computation-span task that were assumed to vary along a rough continuum of the amount of required processing. The results indicated that although a central processor appears to be involved when working-memory tasks require simultaneous storage and processing of information, age-related differences in working memory seem to be determined at least as much by differences in the capacity of storage as by differences in the efficiency of processing.     

Cognitive performance is highly sensitive to prior experience in mice with a learning and memory deficit: failure leads to more failure

The impact of a previously successful or unsuccessful experience on the subsequent acquisition of a related task is not well understood. The nature of past experience may have even greater impact in individuals with learning deficits, as their cognitive processes can be easily disrupted. Mice with a targeted disruption of the alpha and delta isoforms of the cAMP-response element-binding protein (CREB) gene (CREB(alphadelta-)-deficient mice) have a genetic vulnerability to impaired learning and memory that is highly influenced by experimental conditions. Thus, we studied the impact of prior successful and unsuccessful experiences on the degree to which CREB(alphadelta-)-deficient mice exhibit impaired spatial learning and memory in the Morris water maze (MWM). In Experiment 1, we replicated the cognitive deficit of CREB(alphadelta-)-deficient mice when given two trials per day with a 1-min intertrial interval (MWM2), and labeled this experience as a "failure." We rescued the deficit using four trials per day with a 3- to 5-min intertrial interval (MWM4) and labeled this experience a "success." In Experiment 2, a new, naive set of wild-type (WT) and CREB(alphadelta-)-deficient mice were randomly assigned to one of two sequence protocols to assess the influence of a success or a failure on subsequent performance. In Group 1, mice were first exposed to the MWM4 condition, followed by the more difficult MWM2 task. As expected, CREB(alphadelta-)-deficient mice performed well in the MWM4; they also performed well during reversal testing (MWM4R) where the goal location is changed. With this initial successful learning experience, the CREB(alphadelta-)-deficient mice then performed as well as WT mice in the MWM2, the condition in which they are known to be impaired. In contrast, CREB(alphadelta-)-deficient mice in Group 2 had an unsuccessful experience when first exposed to the MWM2 condition, and then also showed impairment in the MWM4, the condition in which they would normally perform well. This deficit was amplified when CREB(alphadelta-)-deficient mice were then tested in the reversal test. Sex differences in learning among CREB(alphadelta-)-deficient mice were amplified upon exposure to an unsuccessful learning experience. These data indicate that, under conditions of cognitive impairment, past experience can-depending on its nature-significantly facilitate or hinder future performance.     

Neurotoxic dorsal CA1 lesions versus 4 VO ischaemic lesions: behavioural comparisons

Anterograde amnesia, a common consequence of transient cerebral ischaemia, has been attributed to cell loss in the hippocampal CA1 subfield. However, variable, widespread damage outside hippocampal CA1 can also occur following ischaemia. We compared the functional consequences of ischaemia and ibotenate acid CA1 lesions on 2 spatial memory tasks (water maze 'place' and 'matching-to-position') to address the possibility that extra-CA1 loss contributes to ischaemia-induced memory deficits in the rat. During place task acquisition, ischaemic rats showed deficits on more measures than ibotenic rats, and during a 1 min probe trial, only ischaemic rats were impaired. On the matching-to-position task, ibotenic rats showed greater impairment than ischaemic rats in terms of one-trial learning, whereas ischaemic rats were more impaired after Trial 2. Ischaemia and ibotenic acid lesions resulted in equivalent CA1 loss, but silver impregnation revealed additional extra-CA1 cell loss in ischaemic rats. Together with the greater behavioural deficits of ischaemic rats, these data indicate a role for extra-CA1 cell loss in ischaemia-induced memory impairments in both animals and humans.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

Differential effects of age on item and associative measures of memory: a meta-analysis

In this meta-analysis, the authors evaluated recent suggestions that older adults' episodic memory impairments are partially due to a reduced ability to encode and retrieve associated/bound units of information. Results of 90 studies of episodic memory for both item and associative information in 3,197 young and 3,192 older adults provided support for the age-related associative/binding deficit suggestion, indicating a larger effect of age on memory for associative information than for item information. Moderators assessed included the type of associations, encoding instructions, materials, and test format. Results indicated an age-related associative deficit in memory for source, context, temporal order, spatial location, and item pairings, in both verbal and nonverbal material. An age-related associative deficit was quite pronounced under intentional learning instructions but was not clearly evident under incidental learning instructions. Finally, test format was also found to moderate the associative deficit, with older adults showing an associative/binding deficit when item memory was evaluated via recognition tests but not when item memory was evaluated via recall tests, in which case the age-related deficits were similar for item and associative information.     

Classically conditioned cardiac responses in "old" and "young" Fischer 344 rats

Male and female Fischer 344 rats, 12 or 26-28 months of age, received two sessions of Pavlovian heart rate conditioning, and were compared with same-sex and same-age controls receiving unpaired presentations of the tone conditional stimulus (CS) and the shock unconditional stimulus (US). Older rats of both sexes demonstrated slower acquisition of the heart rate (HR) conditioned response (CR), and smaller magnitude changes than did the younger animals. Control experiments in 6-, 12-, 24-, and 30-month-old animals indicated that these differences were not due to an impaired sensitivity to the CS or US in the older animals. Results are discussed in terms of their implications for use of this animal model in investigations of age-related deficits in associative learning.     

The effects of aging on the working memory processes of multimodal information

Normal aging is associated with deficits in working memory processes. However, the majority of research has focused on storage or inhibitory processes using unimodal paradigms, without addressing their relationships using different sensory modalities. Hence, we pursued two objectives. First, was to examine the effects of aging on storage and inhibitory processes. Second, was to evaluate aging effects on multisensory integration of visual and auditory stimuli. To this end, young and older participants performed a multimodal task for visual and auditory pairs of stimuli with increasing memory load at encoding and interference during retention. Our results showed an age-related increased vulnerability to interrupting and distracting interference reflecting inhibitory deficits related to the off-line reactivation and on-line suppression of relevant and irrelevant information, respectively. Storage capacity was impaired with increasing task demands in both age groups. Additionally, older adults showed a deficit in multisensory integration, with poorer performance for new visual compared to new auditory information.     

Medial dorsal thalamic lesions and working memory in the rat

Pigmented rats of the DA strain with either radiofrequency or ibotenic acid lesions of the thalamic nucleus medialis dorsalis were postoperatively given nonspatial and spatial tests of working memory. In the nonspatial task, delayed nonmatching-to-sample, rats with both types of thalamic lesions showed acquisition impairments. The subgroup of rats with nucleus medialis dorsalis lesions that were able to reach the acquisition criterion did, however, perform normally when the retention interval was extended to 60 s. In the spatial task, delayed forced-alternation, rats were tested with differing retention intervals and with both spaced and massed trials. Damage to nucleus medialis dorsalis had no effect on acquisition or on spaced trials, but a slight deficit was found in the animals with radiofrequency lesions under the massed trial condition. Much clearer deficits were, however, present in those animals in which the lesion extended appreciably into the anterior thalamic nuclei. The findings indicate that while cellular damage to nucleus medialis dorsalis may disrupt learning, some impairments in tests of spatial working memory attributed to this nucleus may reflect damage to the adjacent anterior thalamic nuclei.     

Working memory in children: tracing age differences and special educational needs to parameters of a formal model

Parameters of a formal working-memory model were estimated for verbal and spatial memory updating of children. The model proposes interference though feature overwriting and through confusion of whole elements as the primary cause of working-memory capacity limits. We tested 2 age groups each containing 1 group of normal intelligence and 1 deficit group. For young children the deficit was developmental dyslexia; for older children it was a general learning difficulty. The interference model predicts less interference through overwriting but more through confusion of whole elements for the dyslexic children than for their age-matched controls. Older children exhibited less interference through confusion of whole elements and a higher processing rate than young children, but general learning difficulty was associated with slower processing than in the age-matched control group. Furthermore, the difference between verbal and spatial updating mapped onto several meaningful dissociations of model parameters.     

Normal aging and the dissociable prototype learning systems

Dissociable prototype learning systems have been demonstrated behaviorally and with neuroimaging in younger adults as well as with patient populations. In A/not-A (AN) prototype learning, participants are shown members of category A during training, and during test are asked to decide whether novel items are in category A or are not in category A. Research suggests that AN learning is mediated by a perceptual learning system. In A/B (AB) prototype learning, participants are shown members of category A and B during training, and during test are asked to decide whether novel items are in category A or category B. In contrast to AN, research suggests that AB learning is mediated by a declarative memory system. The current study examined the effects of normal aging on AN and AB prototype learning. We observed an age-related deficit in AB learning, but an age-related advantage in AN learning. Computational modeling supports one possible interpretation based on narrower selective attentional focus in older adults in the AB task and broader selective attention in the AN task. Neuropsychological testing in older participants suggested that executive functioning and attentional control were associated with better performance in both tasks. However, nonverbal memory was associated with better AN performance, while visual attention was associated with worse AB performance. The results support an interactive memory systems approach and suggest that age-related declines in one memory system can lead to deficits in some tasks, but to enhanced performance in others.     

Double dissociation of pharmacologically induced deficits in visual recognition and visual discrimination learning

Monkeys trained in either one-trial recognition at 8- to 10-min delays or multi-trial discrimination habits with 24-h intertrial intervals received systemic cholinergic and dopaminergic antagonists, scopolamine and haloperidol, respectively, in separate sessions. Recognition memory was impaired markedly by scopolamine but not at all by haloperidol, whereas habit formation was impaired markedly by haloperidol but only minimally by scopolamine. These differential drug effects point to differences in synaptic modification induced by the two neuromodulators that parallel the contrasting properties of the two types of learning, namely, fast acquisition but weak retention of memories versus slow acquisition but durable retention of habits.