Candace J. Ikeda-Douglas

Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study

The effectiveness of two interventions, dietary fortification with antioxidants and a program of behavioral enrichment, was assessed in a longitudinal study of cognitive aging in beagle dogs. A baseline protocol of cognitive testing was used to select four cognitively equivalent groups: control food-control experience (C-C), control food-enriched experience (C-E), antioxidant fortified food-control experience (A-C), and antioxidant fortified food-enriched experience(A-E). We also included two groups of young behaviorally enriched dogs, one receiving the control food and the other the fortified food. Discrimination learning and reversal was assessed after one year of treatment with a size discrimination task, and again after two years with a black/white discrimination task. The four aged groups were comparable at baseline. At one and two years, the aged combined treatment group showed more accurate learning than the other aged groups. Discrimination learning was significantly improved by behavioral enrichment. Reversal learning was improved by both behavioral enrichment and dietary fortification. By contrast, the fortified food had no effect on the young dogs. These results suggest that behavioral enrichment or dietary fortification with antioxidants over a long-duration can slow age-dependent cognitive decline, and that the two treatments together are more effective than either alone in older dogs.

Landmark discrimination learning in the dog: effects of age, an antioxidant fortified food, and cognitive strategy

The landmark discrimination learning test can be used to assess the ability to utilize allocentric spatial information to locate targets. The present experiments examined the role of various factors on performance of a landmark discrimination learning task in beagle dogs. Experiments 1 and 2 looked at the effects of age and food composition. Experiments 3 and 4 were aimed at characterizing the cognitive strategies used in performance on this task and in long-term retention. Cognitively equivalent groups of old and young dogs were placed into either a test group maintained on food enriched with a broad-spectrum of antioxidants and mitochondrial cofactors, or a control group maintained on a complete and balanced food formulated for adult dogs. Following a wash-in period, the dogs were tested on a series of problems, in which reward was obtained when the animal responded selectively to the object closest to a thin wooden block, which served as a landmark. In Experiment 1, dogs were first trained to respond to a landmark placed directly on top of coaster, landmark 0 (L0). In the next phase of testing, the landmark was moved at successively greater distances (1, 4 or 10 cm) away from the reward object. Learning varied as a function of age group, food group, and task. The young dogs learned all of the tasks more quickly than the old dogs. The aged dogs on the enriched food learned L0 significantly more rapidly than aged dogs on control food. A higher proportion of dogs on the enriched food learned the task, when the distance was increased to 1cm. Experiment 2 showed that accuracy decreased with increased distance between the reward object and landmark, and this effect was greater in old animals. Experiment 3 showed stability of performance, despite using a novel landmark, and new locations, indicating that dogs learned the landmark concept. Experiment 4 found age impaired long-term retention of the landmark task. These results indicate that allocentric spatial learning is impaired in an age-dependent manner in dogs, and that age also affects performance when the distance between the landmark and target is increased. In addition, these results both support a role of oxidative damage in the development of age-associated cognitive dysfunction and indicate that short-term administration of a food enriched with supplemental antioxidants and mitochondrial cofactors can partially reverse the deleterious effects of aging on cognition.

Dietary enrichment counteracts age-associated cognitive dysfunction in canines

Advanced age is accompanied by cognitive decline indicative of central nervous system dysfunction. One possibly critical causal factor is oxidative stress. Accordingly, we studied the effects of dietary antioxidants and age in a canine model of aging that parallels the key features of cognitive decline and neuropathology in humans. Old and young animals were placed on either a standard control food, or a food enriched with a broad spectrum of antioxidants and mitochondrial enzymatic cofactors. After 6 months of treatment, the animals were tested on four increasingly difficult oddity discrimination learning problems. The old animals learned more slowly than the young, making significantly more errors. However, this age-associated decline was reduced in the animals fed the enriched food, particularly on the more difficult tasks. These results indicate that maintenance on foods fortified with complex mixtures of antioxidants can partially counteract the deleterious effects of aging on cognition.

Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs

The effects of long-term treatment with both antioxidants and a program of behavioral enrichment were studied as part of a longitudinal investigation of cognitive aging in beagle dogs. Baseline performance on a battery of cognitive tests was used to assign 48 aged dogs (9-12 years) into four cognitively equivalent groups, of 12 animals per group: Group CC (control food-control environment), group CE (control food-enriched environment); Group AC (antioxidant fortified food-control environment); Group AE (fortified food-enriched environment). We also tested a group of young dogs fed the control food and a second group fed the fortified food. Both groups of young dogs received a program of behavioral enrichment. To evaluate the effects of the interventions on cognition after 1 year, the dogs were tested on a size discrimination learning task and subsequently on a size discrimination reversal learning task. Both tasks showed age-sensitivity, with old dogs performing more poorly than young dogs. Both tasks were also improved by both the fortified food and the behavioral enrichment. However, in both instances the treatment effects largely reflected improved performance in the combined treatment group. These results suggest that the effectiveness of antioxidants in attenuating age-dependent cognitive decline is dependent on behavioral and environmental experience.

Visuospatial impairments in aged canines (Canis familiaris): the role of cognitive-behavioral flexibility.

This study used a novel delayed nonmatching-to-position task to compare visuospatial learning and memory in young and aged beagle dogs (Canis familiaris). The task used 3, rather than 2, spatial locations, which markedly increased difficulty. There were striking age differences in acquisition. Most of the aged canines did not learn the task, and those that did showed impaired learning when compared with the young canines. The aged canines also showed reduced maximal working memory capacity compared with the young canines. Analysis of the response patterns of individual canines indicated that the deficits were related to the use of ineffective strategies and inflexibility in strategy modification.

Use of a delayed non-matching to position task to model age-dependent cognitive decline in the dog.

Spatial learning and memory in young and old dogs was studied in a series of experiments using a delayed non-matching to position (DNMP) paradigm. Past research from our laboratory has suggested that aged dogs perform more poorly on a version of the DNMP task compared to young dogs [Head et al., Spatial learning and memory as a function of age in the dog, Behav. Neurosci. 1995;109(5):851-585]. We have now extended these findings by testing a large number of dogs on three different variations of the DNMP paradigm to evaluate different aspects of spatial learning and memory. Our results indicate that: (1) aged dogs show impaired spatial learning compared to young dogs, (2) aged dogs display spatial working memory deficits compared to young dogs, (3) young dogs have a greater maximum working spatial memory capacity than old dogs and (4) we can use the DNMP paradigm to cognitively categorize different subsets of aged dogs. These data indicate that the DNMP paradigm can serve as a valuable tool to evaluate age-dependent cognitive dysfunction in the canine.

Development of spontaneous seizures over extended electrical kindling: I. Electrographic, behavioral, and transfer kindling correlates

The present study was aimed at evaluating an extended kindling model of spontaneous epilepsy. Behavioral and electrographic responses to repeated kindling of either the perforant path or amygdala were monitored for up to 300 trials. Kindling initially led to generalized convulsions equivalent to the level 5 seizure on the rating scale developed by Racine. The evoked seizures became progressively more complex with additional kindling, which was described by a 10-stage classification system. The highest stage (stage 10) was achieved when the kindling stimulation evoked two or more bouts of level 5 seizures combined with running and jumping fits. These more complex seizures developed over the course of amygdala, but not perforant path kindling. Electrographic seizures from both the amygdala and dentate gyrus increased in duration and amplitude during the early phase of kindling, but did not correlate with motor seizure development beyond level 5. During the late phase of kindling, the dentate gyrus afterdischarge amplitude decreased and became dissociated from the behavioral seizures. Manifestations of spontaneously recurring seizures were seen in the majority of animals, but spontaneous seizures of level 4 or greater were observed in only five rats. The second part of this study examined kindling transfer effects, the efficacy of kindling a new site after the completion of the initial (in this case extended) kindling protocol. The effect depended on both primary and secondary site location. When the amygdala served as primary site, perforant path transfer was complete in some animals but absent in others. No transfer occurred in the opposite direction, from the perforant path to the amygdala. Finally, transfer effects in the dentate gyrus, which was tested as tertiary site, were complete. Previous studies have found weaker transfer effects in the dentate when kindling to the standard stage 5 level.

Chronic antioxidant and mitochondrial cofactor administration improves discrimination learning in aged but not young dogs

The present experiment was part of a 3-year longitudinal study examining the effects of age and antioxidant treatment on cognitive decline in beagles. Two size-concept tasks were administered following pretraining on a series of two-choice (six subtests) and three-choice size discrimination tasks. Thirty-nine young and aged dogs were matched for age and cognitive ability then divided into four treatment groups. A combined antioxidant-mitochondrial cofactor treatment led to significantly improved performance in aged dogs on the first subtest of the two-choice size discrimination series. Treated aged dogs did not significantly differ from the young. Aged dogs on the antioxidant diet continued to perform better than aged controls on the second and third subtests, but these effects did not achieve significance. Young dogs performed significantly better than the aged dogs on the second and third subtests. The remaining two-choice tasks of the discrimination series were comparatively easy, leading to a floor effect. The antioxidant animals performed better on the three-choice size discrimination, but not on the two size-concept tasks. Antioxidants improved the performance of aged dogs on the initial learning tests, suggesting a selective improvement of factors related to the aging process and specific cognitive processes rather than general cognitive enhancement.

A comparison of egocentric and allocentric age-dependent spatial learning in the beagle dog

Spatial discriminations can be performed using either egocentric information based on body position or allocentric information based on the position of landmarks in the environment. Beagle dogs ranging from 2 to 16 years of age were tested for their ability to learn a novel egocentric spatial discrimination task that used two identical blocks paired in three possible spatial positions (i.e. left, center and right). Dogs were rewarded for responding to an object furthest to either their left or right side. Therefore, when the center location was used, it was correct on half of the trials and incorrect on the other half. Upon successful acquisition of the task, the reward contingencies were reversed, and the dogs were rewarded for responding to the opposite side. A subset of dogs was also tested on an allocentric spatial discrimination task, landmark discrimination. Egocentric spatial reversal learning and allocentric discrimination learning both showed a significant age-dependent decline, while initial egocentric learning appeared to be age-insensitive. Intra-subject correlation analyses revealed a significant relationship between egocentric reversal learning and allocentric learning. However, the correlation only accounted for a small proportion of the variance, suggesting that although there might be some common mechanism underlying acquisition of the two tasks, additional unique neural substrates were involved depending on whether allocentric or egocentric spatial information processing was required.

Effects of extended electrical kindling on exploratory behavior and spatial learning

Short-term electrical kindling, a widely used experimental model of epilepsy, appears to have little effect on behavior. The effects of extended kindling are largely unknown. Rats implanted with kindling electrodes in amygdala (AM) or perforant path (PP) received 300 kindling trials over approximately 7 months, and were tested in the Morris watermaze after a 7-10 day recovery period. Kindled animals were impaired during the initial training on hidden-platform acquisition, but not in retention of platform location. No deficits were found in acquiring a new hidden-platform location, latency to reach a visible-platform, or in swim speed. Open-field activity showed a sustained increase when tested during kindling, but only a transient increase when tested following suspension of kindling. Similar results were obtained for both AM and PP kindled animals. Hence, long-term kindling of both of these sites produced behavioral changes that were transient in nature. Further, these results also indicate that propagation of seizure activity from remote sites can alter hippocampally-mediated or related behavior.