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Norton W Milgram

Publications and source records attributed to Norton W Milgram.

At least 19 recordsLinked to original sources
PubMed2006

Region specific neuron loss in the aged canine hippocampus is reduced by enrichment.

Neuron loss within the hippocampus and entorhinal cortex occurs as a function of age in humans. We first tested the hypothesis that neuron loss occurs in the aged dog. The total unilateral number of neurons in the canine entorhinal cortex and subdivisions of the hippocampus from the left hemisphere were estimated using the optical fractionator. The brains from 5 old (13.0-15.0 years old) and 5 young (3.4-4.5 years old) beagle dogs were analyzed. The hilus of the hippocampus showed a significant loss of neurons (approximately 30%) in the aged dog brain compared to young. Differences were not detected in the remaining hippocampal subfields and entorhinal cortex. We further tested the hypothesis that an antioxidant fortified food or behavioral enrichment would reduce the age-related loss of hilar neurons. Behaviorally enriched aged dogs had more neurons in the hilus (approximately 18%) compared to aged controls. These results suggest that the aged canine hippocampus in the left hemisphere shows selective neuron loss and that behavioral enrichment may reduce this loss.

Age Factors↗
PubMed2006

Neuroprotective effects of cognitive enrichment.

Cognitive enrichment early in life, as indicated by level of education, complexity of work environment or nature of leisure activities, appears to protect against the development of age-associated cognitive decline and also dementia. These effects are more robust for measures of crystallized intelligence than for measures of fluid intelligence and depend on the ability of the brain to compensate for pathological changes associated with aging. This compensatory ability is referred to as cognitive reserve. The cognitive reserve hypothesis suggests that cognitive enrichment promotes utilization of available functions. Alternatively, late life cognitive changes in cognition may be linked to a factor, such as cholinergic dysfunction, that is also present early in life and contributes to the reduced levels of early life cognitive enrichment. Beneficial effects of environmental enrichment early in life have also been observed in rodents and primates. Research with rodents indicates that these changes have structural correlates, which likely include increased synapses in specific brain regions. Dogs also show age-dependent cognitive decline, and both longitudinal and cross-sectional studies indicate that this decline can be attenuated by cognitive enrichment. Furthermore, cognitive enrichment has differential effects, improving some functions more than others. From a neurobiological perspective, behavioral enrichment in the dog may act to promote neurogenesis later in life. This can be distinguished from nutritional interventions with antioxidants, which appear to attenuate the development of neuropathology. These results suggest that a combination of behavioral and nutritional or pharmacological interventions may be optimal for reducing the rate of age-dependent cognitive decline.

Aging↗
PubMed2006

Visuospatial function in the beagle dog: an early marker of cognitive decline in a model of human aging and dementia.

Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimer's disease. Similar to humans, aged dogs show visuospatial learning and memory deficits (). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-beta (Abeta) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Abeta oligomers or cholinergic deficits, are likely contributing to the early impairment.

Aging↗
PubMed2006

Extensive spatial training does not negate age differences in response latency.

Previously, Nippak et al. [Nippak, P.M.D., Chan, A.D.F., Campbell, Z., Muggenburg, B., Head, E., Ikeda-Douglas, C., Murphy, H., Cotman, C.W., Milgram, N.W., 2003. Response latency in the canine: mental ability or mental strategy? Behav. Neurosci. 117 (5), 1066-1075] reported that young dogs respond significantly slower than aged dogs during the acquisition of a three-component delayed non-match to position (3-DNMP) task. Thus, we examined how age influences response latency (RL) when animals are trained extensively on the 3-DNMP task. Animals were separated into two groups based on their task sophistication. The first group comprised young (N=5) and aged (N=10) dogs that received extensive spatial training on a two-component delayed non-match to position task (2-DNMP) before 3-DNMP testing, while the second group of young (N=8) and aged (N=11) animals received extensive training on a variety of other non-spatial cognitive tasks between each 3-DNMP test period. RL age differences were absent following extensive 3-DNMP testing; however, other age-dependent performance differences emerged: all young animals learned the task and displayed RL slowing and superior response accuracy (RA) on the center-incorrect (CI) subtest, while several aged animals failed to learn the task and displayed no RL or RA subtest variations even when they acquired the task. Toates's [Toates, F., 1998. The interaction of cognitive and stimulus-response processes in the control of behaviour, Neurosci. Biobehav. Rev. 22 (1), 59-83] theory of RL and mental strategy was proposed to explain these age differences in response strategies: the fast-responding aged animals utilized stimulus-response strategies, while the slow-responding young animals adopted cognitive strategies, a specific requirement for solving the CI subtest.

Aging↗
PubMed2006

Immunization with fibrillar Abeta(1-42) in young and aged canines: Antibody generation and characteristics, and effects on CSF and brain Abeta.

We describe a study testing fibrillar beta-amyloid(1-42) (Abeta42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with Abeta42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG2 and IgM antibody responses, which were specific for the Abeta(11-30) region of Abeta(1-42). Next, 3 aged beagles (8.9-13.8 years) were immunized 4 times with Abeta(42) and a Th2 adjuvant (Alum). We observed an acute increase in IgG2, a slower increase in IgG1 and Abeta antibodies of broader specificity (Abeta(1-15>) Abeta(11-30>) Abeta(6-20)). A nonsignificant increase in CSF Abeta(1-40) and decrease in Abeta(1-40/1-42) in cortex was detected. Canines may be a useful system for testing an Abeta vaccine.

Adjuvants, Immunologic↗
PubMed2005

Application of an automated voxel-based morphometry technique to assess regional gray and white matter brain atrophy in a canine model of aging.

In recent years, voxel-based morphometry (VBM) has emerged as a technique to examine regional brain changes associated with normal and pathological aging. Despite its popularity in studies of human aging, application of VBM to animal models of brain aging is rare. In the present study, VBM techniques were developed to validate earlier region of interest (ROI) measures of brain aging in the dog and to provide a more comprehensive analysis of local changes in a canine model of brain aging. Consistent with previous findings, frontal lobe atrophy increased with age, most notably in aged male dogs. Age-related gray matter reductions were also observed in parietal and temporal lobes, thalamus, cerebellum, and brainstem. Temporal lobe atrophy was particularly prominent in old females. A number of age-related changes in white matter not previously explored in the dog were also identified with VBM. Specifically, aged males exhibited greater decreases in the internal capsula and cranial nerve bundles compared to decreased volumes in the alveus of the hippocampus in old female dogs. Together, the present results indicate that application of VBM techniques in a canine model of aging yields more comprehensive information regarding topographical patterns of brain aging in male and female dogs than previously reported using traditional manual ROI methods.

Aging↗
PubMed2005

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.

Aging↗
PubMed2005

An investigation of the relationship between response latency across several cognitive tasks in the beagle dog.

Response latencies (RLs) extracted from simple motor tasks are a commonly used index of human intelligence. To date few human or animal studies have investigated the relationship between an individuals RL scores across a number of diverse cognitive tasks: Does RL remain consistent between individuals across several cognitive domains? Thus, the current study examined how RL measures gathered from beagle dogs (n=13) tested on three different cognitive tasks were related. RL scores were collected following both discrimination and reversal learning and a test of visuospatial memory, the 3 component delayed non-matching to position (3-DNMP) task. RL scores were recorded from the time the choice stimulus was presented until the animal selected a response. Results indicated that strong correlations emerged between 3-DNMP RLs and both the discrimination and reversal RLs, indicating that animals that responded fast on the 3-DNMP task also responded fast on the discrimination and reversal tasks. Interestingly, 3-DNMP RLs were more strongly correlated with reversal learning RLs. Finally, when mean RL performance across the three tasks was examined, strong RL differences emerged indicating that animals displayed significantly slower RLs on the 3-DNMP task than on the discrimination task, while reversal RLs remained indistinguishable from both. In conclusion, RLs show high between task correlations, indicating individual differences, and also vary between tasks, probably because of differences in task difficulty. These results further validate the use of RLs as an index of cognition, and also highlight the importance of further studies using animal models.

Animals↗
PubMed2005

A novel method for assessing contrast sensitivity in the beagle dog is sensitive to age and an antioxidant enriched food.

Tasks requiring visual discrimination are commonly used in assessment of canine cognitive function. However, little is known about canine visual processing, and virtually nothing is known about the effects of age on canine visual function. This study describes a novel behavioural method developed to assess one aspect of canine visual function, namely contrast sensitivity. Four age groups (young, middle aged, old, and senior) were studied. We also included a group of middle aged to old animals that had been maintained for at least 4 years on a specially formulated food containing a broad spectrum of antioxidants and mitochondrial cofactors. Performance of this group was compared with a group in the same age range maintained on a control diet. In the first phase, all animals were trained to discriminate between two high contrast shapes. In the second phase, contrast was progressively reduced by increasing the luminance of the shapes. Performance decreased as a function of age, but the differences did not achieve statistical significance, possibly because of a small sample size in the young group. All age groups were able to acquire the initial discrimination, although the two older age groups showed slower learning. Errors increased with decreasing contrast with the maximal number of errors for the 1% contrast shape. Also, all animals on the antioxidant diet learned the task and had significantly fewer errors at the high contrast compared with the animals on the control diet. The initial results suggest that contrast sensitivity deteriorates with age in the canine while form perception is largely unaffected by age.

Aging↗
PubMed2005

Effects of scopolamine challenge on regional cerebral blood volume. A pharmacological model to validate the use of contrast enhanced magnetic resonance imaging to assess cerebral blood volume in a canine model of aging.

Cognitive impairment resulting from disruption of cholinergic function may occur through modulation of cerebrovascular volume (CBV). In the present study, dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) was used to examine cerebrovascular volume in young and old dogs during baseline and after administration of a cholinergic antagonist (scopolamine). In the first study, 24 animals (2-15 years of age) were given a baseline scan followed by a second scan after scopolamine administration (30 microg/kg). Gray matter rCBV was significantly higher than white matter rCBV during baseline and scopolamine administration. In the second study a subset of 7 dogs (4 young and 3 old) received scopolamine before anesthesia was induced for a second DSC-MRI scan. Consistent with the first study, gray matter rCBV was significantly higher than white matter rCBV. Scopolamine administered before anesthesia however, resulted in higher rCBV values compared to baseline in cerebral gray matter. Additionally, rCBVs were higher in young dogs at baseline in gray and white matter and marginally higher in gray matter when scopolamine was administered before anesthesia. These results indicate that in the dog, rCBV varies with brain compartment, decreases with age, and that DSC-MRI provides a measure of cerebrovascular function which may be related to age-dependent changes in cognition, brain structure, and neuropathology.

Aging↗
PubMed2005

Further evidence for the cholinergic hypothesis of aging and dementia from the canine model of aging.

Memory decline in human aging and dementia is linked to dysfunction of the cholinergic system. Aging dogs demonstrate cognitive impairments and neuropathology that models human aging and dementia. This paper reviews recent evidence suggesting cholinergic involvement in canine cognitive aging based on studies with the anti-cholinergic drug, scopolamine, and a novel acetylcholinesterase inhibitor, phenserine. In particular, we examine: (1) the cognitive specificity of scopolamine's impairment in dogs, (2) the effect of age on scopolamine impairment and (3) the effect of phenserine on cognitive performance in dogs. Our findings indicate that working memory performance is disrupted by scopolamine at doses that do not disrupt non-cognitive behavior or long-term, semantic-like, memory, as indicated by performance of previously learned discriminations. This pattern of deficits is also seen in human and canine aging. We demonstrate that aged dogs are more sensitive to the impairing effects of scopolamine than young dogs, suggesting a decrease in cholinergic tone with increasing age. Dogs receiving phenserine demonstrate improved learning and memory compared to placebo controls. Our findings suggest that cholinergic decline could result in memory impairment, but that the memory impairment may be secondary to deficits in attention and/or encoding of new information. Together, these results suggest that the canine cholinergic system declines with age and that the aged dog is a unique model for screening therapeutics and for examining the relationship between amyloid pathology and cholinergic dysfunction in age-dependent cognitive decline.

Acetylcholine↗
PubMed2005

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.

Age Factors↗
PubMed2005

Effect of feeding patterns on performance of a visuospatial memory task in the beagle dog: a novel cognitive-based protocol for assessing satiety.

The assessment of appetite suppressing effects, or satiating effects, of drugs or other treatments is typically based on the measurement of food consumption and body weight. The present study describes a novel cognitive-based protocol for assessing satiety in the dog based on response latency and performance accuracy on a canine test of spatial working memory, the three-component delayed-non-matching-to-position task (3cDNMP). We hypothesized that satiety, produced by providing food prior to testing, would reduce motivation to respond quickly and accurately on this food-reinforced task. Dogs were first over-trained on a variable-delay version of the 3cDNMP task. They were then pre-fed with either a single or a double portion of food prior to being tested on the same task. Pre-feeding slowed response latency, but had no effect on performance accuracy. A more pronounced increase in response latency was observed in young dogs than in old dogs when offered double portions of food. These results suggest, first, that spatial working memory capability is independent of motivation; second, that satiety is age sensitive; and third, that a cognitive protocol can provide a reliable method for evaluating the satiating effects of various foods and other compounds in the dog.

Aging↗
PubMed2005

The canine model of human cognitive aging and dementia: pharmacological validity of the model for assessment of human cognitive-enhancing drugs.

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.

Aging↗
PubMed2004

Frontal lobe volume, function, and beta-amyloid pathology in a canine model of aging.

Application of magnetic resonance imaging (MRI) techniques reveals that human brain aging varies across cortical regions. One area particularly sensitive to normal aging is the frontal lobes. In vitro neuropathological studies and behavioral measures in a canine model of aging previously suggested that the frontal lobes of the dog might be sensitive to aging. In the present study, MRI scans were acquired to compare age-related changes in frontal lobe volume with changes in executive functions and beta-amyloid pathology in the frontal cortex of beagle dogs aged 3 months to 15 years. Decreases in total brain volume appeared only in senior dogs (aged 12 years and older), whereas frontal lobe atrophy developed earlier, appearing in the old dogs (aged 8-11 years). Hippocampal volume also declined with age, but not occipital lobe volume past maturity. Reduced frontal lobe volume correlated with impaired performance on measures of executive function, including inhibitory control and complex working memory, and with increased beta-amyloid accumulation in the frontal cortex. Age-related hippocampal atrophy also correlated with complex working memory but not inhibitory control, whereas occipital lobe volume did not correlate with any cognitive measure. These findings are consistent with the frontal lobe theory of aging in humans, which suggests that the frontal lobes and functions subserved by this region are compromised early in aging.

Aging↗
PubMed2004

Concept abstraction in the aging dog: development of a protocol using successive discrimination and size concept tasks.

The present study examined the effects of age on concept learning in beagle dogs. In experiment one, subjects were tested on a series of 2-choice size discrimination (2CSD) tasks, in which the correct response was to always approach the larger or smaller of the two blocks. Compared to old and senior dogs, young and middle-aged dogs solved the initial training subtest faster and were more successful at transferring this learning to subsequent tests. The second experiment extended the task by using three rather than two objects and introducing novel objects to test concept acquisition. Young and middle-aged dogs made fewer errors than old or senior dogs on a 3-choice size discrimination (3CSD) task. Transfer performance was above chance for all four groups on the 3CSD and first 3-choice size concept (CSC) task and for the young dogs on the second 3CSC but did not differ from the original learning criterion in any group. Age impairments in concept learning may account for differences in transfer performance on both 3CSC tests.

Age Factors↗