PubMed Health⌕ Search

Biomedical subjects

N W Milgram

Publications and source records attributed to N W Milgram.

At least 19 recordsLinked to original sources
PubMed2005

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.

Age Factors↗
PubMed2005

Changes in phosphorylation of the NMDA receptor in the rat hippocampus induced by status epilepticus.

Systemic administration of pilocarpine preceded by lithium induces status epilepticus (SE) that results in neurodegeneration and may lead to the development of spontaneous recurrent seizures. We investigated the effect of Li/pilocarpine-induced SE on phosphorylation of the NMDA receptor in rat hippocampus. Phosphorylation of NR1 by PKC on Ser890 was decreased to 45% of control values immediately following 1 h of SE. During the first 3 h following the termination of SE, phosphorylation of Ser890 increased 4-fold before declining to control values by 24 h. Phosphorylation of NR1 by PKA was also depressed relative to controls immediately following SE and transiently increased above control values upon the termination of SE. SE was accompanied by a general increase in tyrosine phosphorylation of hippocampal proteins that lasted for several hours following the termination of seizures. Tyrosine phosphorylation of the NR2A and NR2B subunits of the NMDAR increased 3-4-fold over control values during SE, continued to increase during the first hour following SE and then declined to control levels by 24 h. SE resulted in the activation of Src and Pyk2 associated with the postsynaptic apparatus, suggesting a role for these enzymes in the SE-induced increase in tyrosine phosphorylation. Changes in phosphorylation of the NMDA receptor may play a role in the pathophysiological consequences of SE.

Animals↗
PubMed2004

Dose-specific effects of scopolamine on canine cognition: impairment of visuospatial memory, but not visuospatial discrimination.

RATIONALE: The cholinergic system is linked extensively to memory, but its exact role remains controversial. In particular, scopolamine-induced impairment in rodents is not task specific, which may be due to difficulty in developing rodent protocols to assess deficits in recent memory, in which the remembered event is brief and distinct, and/or to non-specific behavioral impairment. OBJECTIVES: The present study sought to determine whether scopolamine-induced deficits in recent memory, using a working memory task, could be dose-specifically dissociated from deficits in associative memory in dogs. METHODS: A Latin-square design was used to determine the effect of scopolamine (5, 10 and 15 microg/kg; SC) on a variable delayed-non-matching-to-position (DNMP) task, which assesses visuospatial working memory. Subsequently, the minimal effective dose (15 microg/kg; SC) was administered prior to testing on a landmark discrimination task, which provides a measure of allocentric spatial ability, a black-white discrimination task, an oddity discrimination task and tests of exploratory behavior. We also investigated the effects of a 30 microg/kg dose (SC) on tests of oddity discrimination and behavioral activity. RESULTS: A 15 microg/kg dose produced significant impairment on the DNMP task, but did not affect performance of any discrimination task and did not alter behavior on tests of open field or curiosity. A 30 microg/kg dose caused disruption on discrimination performance and on open field measures. CONCLUSIONS: Working memory performance is most sensitive to scopolamine-induced impairment and can be dissociated from scopolamine-induced deficits in discrimination performance and non-cognitive behaviors. The present results indicate that scopolamine-induced impairments of working memory in the dog can serve as a model of age-related cholinergic dysfunction.

Aging↗
PubMed2004

A novel cognitive palatability assessment protocol for dogs.

Assessment of canine palatability is important for both the pet food and pharmaceutical industries; however, the current palatability assessment protocols are limited in their utility. The most common technique, the two-pan test, does not control for the satiating effects of food and may not be useful for long-term palatability analysis because nutritional or caloric characteristics of the diets may interfere with the results. Furthermore, the large quantities of foods consumed may be detrimental to the health of animals that do not self-limit their food intake. The purpose of this study was to determine whether a cognitive protocol could be used to determine food palatability in dogs. Five beagle dogs were trained on a three-choice object-discrimination learning task. After establishing object preferences, the preferred object was associated with no reward, a second object was associated with the dog's normal laboratory diet (Purina Agribrands Canine Lab Chow No. 5006; Agribrands Purina Canada, Inc., Woodstock, ON, Canada), and the third object was associated with a commercial (Hill's P/D; Hill's Pet Nutrition Inc., Topeka, KS) diet. In the discrimination-training phase, dogs were trained until they learned to avoid the no-reward object. They were subsequently given an additional 20 test sessions, which were used to determine food preference. In the reversal phase, which involved reversal learning, the object-food associations were modified, such that the object that was previously associated with Hill's P/D diet was now associated with the normal laboratory diet and vice versa. Once the dogs learned to avoid the no-reward object, they were tested for an additional 20 sessions. All subjects learned to avoid the no-reward object during the initial learning, and the number of choices to the object associated with the Hill's P/D diet was greater than the number of choices to the objects associated with the dry laboratory diet (P < 0.05) and no reward (P < 0.05), indicating a strong preference for the Hill's P/D diet. The object preferences were reversed in only three of five dogs when the food-choice associations were reversed, although the two phases did not differ significantly from one another. The protocol in the present study provides a robust measure of food palatability and circumvents many of the limitations associated with other palatability assessment techniques. The present protocol should be useful as a replacement or adjunct to other tests of palatability, but requires further validation by comparing the assessment of more similar and novel foods directly with other palatability tests.

Animal Feed↗
PubMed2002

Oxidative damage increases with age in a canine model of human brain aging.

We assayed levels of lipid peroxidation, protein carbonyl formation, glutamine synthetase (GS) activity and both oxidized and reduced glutathione to study the link between oxidative damage, aging and beta-amyloid (Abeta) in the canine brain. The aged canine brain, a model of human brain aging, naturally develops extensive diffuse deposits of human-type Abeta. Abeta was measured in immunostained prefrontal cortex from 19 beagle dogs (4-15 years). Increased malondialdehyde (MDA), which indicates increased lipid peroxidation, was observed in the prefrontal cortex and serum but not in cerebrospinal fluid (CSF). Oxidative damage to proteins (carbonyl formation) also increased in brain. An age-dependent decline in GS activity, an enzyme vulnerable to oxidative damage, and in the level of glutathione (GSH) was observed in the prefrontal cortex. MDA level in serum correlated with MDA accumulation in the prefrontal cortex. Although 11/19 animals exhibited Abeta, the extent of deposition did not correlate with any of the oxidative damage measures, suggesting that each form of neuropathology accumulates in parallel with age. This evidence of widespread oxidative damage and Abeta deposition is further justification for using the canine model for studying human brain aging and neurodegenerative diseases.

Aging↗
PubMed2001

Seizure activity results in increased tyrosine phosphorylation of the N-methyl-D-aspartate receptor in the hippocampus.

Systemic administration of kainic acid (KA) induces status epilepticus (SE) that causes neurodegeneration and may subsequently lead to spontaneous recurrent seizures. We investigated the effects of KA-induced SE on tyrosine phosphorylation and solubility properties of the NMDA receptor. Following 1 h of SE, total protein tyrosine phosphorylation was elevated in both the hippocampus and frontal cortex relative to controls. Tyrosine phosphorylation of the NMDA receptor subunits NR2A and NR2B was also enhanced following SE. Animals that received KA but did not develop SE, did not exhibit increased tyrosine phosphorylation. SE resulted in a decrease in the solubility of NMDA receptor subunits and of PSD-95 in 1% deoxycholate. In contrast, the detergent solubility of AMPA and kainate receptors was not affected. These findings demonstrate that SE alters tyrosine phosphorylation of the NMDA receptor, and indicate that the interaction of the NMDA receptor with other components of the NMDA receptor complex are altered as a consequence of seizure activity.

Animals↗
PubMed2001

The ability to smell remains intact, but does not recover, after olfactory bulb lesions.

We examined two unresolved issues regarding the influence of olfactory bulb lesions on the ability to smell. First, we asked whether the sense of smell remains intact or recovers after incomplete and complete removal of both olfactory bulbs and second, whether the qualitative perception of smell changes after lesion. Rats were trained to perform a four-choice olfactory discrimination task and were subsequently prepared with either medium, large, or complete bilateral olfactory bulb lesions. They were retested after a recovery period of either 6 or 22 weeks. The lesion effect depended on lesion size, and not on recovery interval. Animals with complete lesions showed no retention, and a failure to relearn, regardless of the recovery interval. Animals with incomplete lesions showed virtually perfect retention. These results, therefore, indicate first that the sense of smell remains intact following extensive olfactory bulb lesions, and that a previously acquired discrimination is permanently lost after complete olfactory bulb lesions.

Animals↗
PubMed2000

Oral administration of adrafinil improves discrimination learning in aged beagle dogs.

Aged beagle dogs were trained on either a size or intensity discrimination task 2 h following treatment with either 20 mg/kg of adrafinil or a placebo control. Training continued until the dogs reached a predetermined criterion level of performance, or failed to acquire the task after 40 sessions. The treatments and tasks were then reversed, with both the test order and treatment order counterbalanced. Thus, half of the animals were first tested on the intensity discrimination, and half of these were first tested under adrafinil. Treatment with adrafinil produced significant improvement in learning, as indicated by a decrease in both errors and trials to criterion. An effect of adrafinil on motivation may partially account for these findings; however, adrafinil did not significantly affect response latency. Adrafinil is believed to serve as an alpha-1 adrenoceptor agonist. The improved learning may also result from enhancement of vigilance due to facilitation of noradrenergic transmission in the central nervous system.

Administration, Oral↗
PubMed2000

Behavioral activating effects of adrafinil in aged canines.

Adrafinil, a vigilance enhancing pharmaceutical, was administered to aged dogs for 14 consecutive days at doses of 10, 20, 30, or 40 mg/kg using a crossover design. The effects on spontaneous behavior in a 10-min canine open-field test were systematically recorded every fourth day, starting with day 1 of treatment. The open field tests were given 2 or 10 h following oral administration of capsules containing either adrafinil or lactose, the placebo control. Adrafinil caused an increase in locomotor activity at the three highest doses at both the 2- and 10-h intervals and during both the first (days 1 and 5) and second treatment week (days 9 and 13). Adrafinil also caused a transient increase in directed sniffing. At the highest dose level, adrafinil caused a decrease in urination frequency. The increased locomotion was generally unaccompanied by stereotypical behavior in the test session. There was some variability; a subpopulation of animals showed either no effect, or decreased locomotion. The individual differences were correlated with changes in serum levels of adrafinil 10 h following treatment.

Aging↗
PubMed2000

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.

Age Factors↗
PubMed2000

The canine as a model of human cognitive aging: recent developments.

1. Aged dogs display many of the cognitive impairments associated with aging and dementia. 2. Aged dogs, like humans, display a wide range of individual variability in cognitive functioning (i.e., different cognitive functions decline at different rates in aged dogs). 3. Different categories of aged canines can be identified on the basis of neuropsychological test performance, and these categories can be used to model different subgroups of aged humans (i.e., dementia, mild cognitive impairment and successful aging). 4. Additional research is required to further validate the dog as a model of human cognitive aging and dementia.

Aging↗
PubMed2000

Development of a protocol for studying object recognition memory in the dog.

1. Dogs had considerable difficulty learning a delayed-non-matching-to sample task at a short delay (approximately 5 seconds) for an extended period (900 trials). Only 3 of 19 dogs met the learning criterion. 2. Acquisition on the DNMS task was markedly improved when a pause was introduced on presentation of the stimulus objects, when the objects were approximately 30 cm from the dog; eleven of 16 dogs learned the task within 600 trials. 3. Dogs learned the task more rapidly at 20 and 30 second delays than at 10-second delays. This indicates a transfer of learning. 4. Dogs that did learn the task were able to perform at accuracy greater than 85% at delays of 150 and 200 seconds. At a 5-minute delay, performance was at 75%. 5. When the animals were switched to a repeated object paradigm, accuracy markedly declined. 6. The improved performance produced by introduction of the pause is attributable to: (1) presenting the object at a distance longer than the dogs' near point, and (2) allowing increased processing time.

Animals↗
PubMed2000

Adrafinil: effects on behavior and cognition in aged canines.

1. Adrafmil is a novel vigilance promoting agent developed in France by Louis Lafon Laboratories. 2. Adrafinil causes increased locomotion without producing stereotypical activity in canines tested in an open field. 3. The effectiveness of a single treatment is long-lasting, and the effectiveness persists over repeated treatments. 4. Acquisition of a size discrimination problem is enhanced by adrafinil. This may be linked to performance motivation. 5. Adrafinil causes a long-lasting increase in high frequency electroencephalographic activity recorded from cortical electrodes. 6. These results indicate that adrafinil is novel behavioral stimulant with cognitive enhancing potential. The underlying mechanisms of action are still unknown.

Aging↗
PubMed2000

Ultrastructural evidence of fibrillar beta-amyloid associated with neuronal membranes in behaviorally characterized aged dog brains.

The aged dog brain accumulates beta-amyloid in the form of diffuse senile plaques, which provides a potentially useful in vivo model system for studying the events surrounding the deposition of beta-amyloid. We used postembedding immunocytochemistry at the electron microscopic level to determine the subcellular distribution of beta-amyloid 1-40 and beta-amyloid 1-42 peptides in the prefrontal and parietal cortex of behaviorally characterized dogs ranging in age from one to 17 years. Immunogold particles signaling beta-amyloid 1-42 occurred over intracellular and extracellular fibrils that were approximately 8 nm in width. Intracellular beta-amyloid 1-42 fibrils were found in close proximity to glial fibrillary acidic protein fibers within astrocytes, but only in cells with signs of plasma membrane disruption. Neuronal labeling of beta-amyloid 1-42 appears to be associated with the plasma membrane. Membrane-bound beta-amyloid 1-42 occurs in the form of fine fibrils that are embedded in the dendritic membrane and appear to project into the extracellular space as determined by quantitative analysis of the immunogold particle distribution. Bundles of beta-amyloid 1-42 were also closely associated and/or integrated with degenerating myelin sheaths of axons. In one dog that was impaired on several cognitive tasks, extensive beta-amyloid 1-42 deposition was associated with microvacuolar changes and vascular pathology. The present findings suggest that beta-amyloid 1-42 may be generated at the dendritic plasma membrane as well as in intracellular compartments. The close association between beta-amyloid 1-42 and destroyed myelin suggests one possible new mechanism by which beta-amyloid 1-42 induces neurodegeneration.

Amyloid beta-Peptides↗
PubMed2000

Comparison of the effects of adrafinil, propentofylline, and nicergoline on behavior in aged dogs.

OBJECTIVE: To compare the efficacy of adrafinil, propentofylline, and nicergoline for enhancing behavior of aged dogs. ANIMALS: 36 Beagles between 9 and 16 years old. PROCEDURE: Dogs were randomly assigned to receive adrafinil (20 mg/kg of body weight, PO, q 24 h; n = 12), propentofylline (5 mg/kg, PO, q 12 h; 12), or nicergoline (0.5 mg/kg, PO, q 24 h; 12) for 33 days. Baseline behaviors in an open field and in kennels (home cage) were recorded before treatment. After treatment, behaviors in the open field were recorded 2 hours after drug administration on days 2, 15, and 28, and 10 hours after administration on days 7, 20, and 33. Behaviors in the home cage were recorded 2 and 7 hours after drug administration on days 4, 17, and 30. RESULTS: Treatment with adrafinil resulted in a significant increase in locomotion in each of the open-field tests and an increase in locomotion in the home cage. This latter increase was smaller and more variable than that in the open field. Locomotion was not affected by treatment with propentofylline or nicergoline. In the open field, sniffing decreased over time in all 3 groups, but the largest decline was observed in the propentofylline group. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with adrafinil may improve the quality of life of aged dogs by increasing exploratory behavior and alertness.

Adrenergic alpha-Antagonists↗
PubMed1999

The long lasting effects of electrical simulation of the medial preoptic area and medial amygdala on maternal behavior in female rats.

A program of repeated electrical (kindling-like) stimulation of the medial preoptic area (MPOA) or the medial amygdala (MedAmyg) on maternal and other behaviors were investigated. Stimulation was applied daily for 14 days (or until a stage 3 motor seizure was observed) using 2 s trains of biphasic square wave pulses at 60 Hz, 1 ms duration and 300-500 microA. Confirmation of afterdischarge using these parametres was established. In the first experiment, maternally experienced (but not post-partum) MedAmyg stimulated animals became maternal more slowly than did MedAmyg not stimulated animals or than MPOA stimulated animals. In the second experiment, virgin animals were used. MPOA stimulation enhanced the female's preference for pup associated environments in the conditioned place preference (CPP) paradigm. MedAmyg stimulation had no effect on CPP performance, but produced a decreased preference for pup odors in a modified hole board test and increased 'anxiety' in the open field. These results confirm that the MPOA and the MedAmyg are involved in facilitating and attenuating maternal responsiveness and related (precursor?) behaviors, respectively. It appears that chronic (kindling-like) stimulation of these neural substrates enhances their functions.

Amygdala↗
PubMed1999

Instability of dentate gyrus field potentials in awake and anesthetized rats.

Adult male Long-Evans rats were prepared with stimulating and recording electrodes in the perforant path and dentate gyrus, respectively. Urethane-anesthetized acute (ACU) preparations and chronically-implanted freely-moving (CHR) animals received moderate-intensity (50-75% of maximum) stimulation pulses every 15-20 s for 4-5 hr in order to assess the stability of evoked field potentials. Significant increases in both population spike amplitude (+6.3%/hr) and EPSP slope (+2.5%/hr) were seen over the course of testing in the ACU group as a whole, while the CHR group showed significant decreases in EPSP slope (-3.3%/hr) but not spike (-1.2%/hr). Thus, both preparations were unstable, though the group mean drift differed in direction. Field potential drift was also affected by body temperature and stimulation intensity; drift was significantly greater when temperature was not controlled, and responses to moderate-intensity stimulation tended to be less stable than responses to high-intensity pulses. Our results indicate that a drift of 4-6% per hour in individual subjects is common; in unheated acute preparations, drift can equal or exceed 20% per hour (3/7 cases). These findings show that response instability can pose significant problems for electrophysiological investigations of neural plasticity.

Anesthetics↗