Dietary and Behavioral Interventions Protect against Age Related Activation of Caspase Cascades in the Canine Brain

Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aβ accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aβ, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON – control environment/control diet, AOX– control environment/antioxidant diet, ENR – enriched environment/control diet, AOX/ENR– enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging

Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs

Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was to determine if canines show age-related decline in their ability to perform a novel simultaneous visual search task. Three groups of canines were included: a young group (N = 10; 3 to 4.5 years), an old group (N = 10; 8 to 9.5 years), and a senior group (N = 8; 11 to 15.3 years). Subjects were first tested for their ability to learn a simple two-choice discrimination task, followed by the visual search task. Attentional demands in the task were manipulated by varying the number of distracter items; dogs received an equal number of trials with either zero, one, two, or three distracters. Performance on the two-choice discrimination task varied with age, with senior canines making significantly more errors than the young. Performance accuracy on the visual search task also varied with age; senior animals were significantly impaired compared to both the young and old, and old canines were intermediate in performance between young and senior. Accuracy decreased significantly with added distracters in all age groups. These results suggest that aging impairs the ability of canines to discriminate between task-relevant and -irrelevant stimuli. This is likely to be derived from impairments in cognitive domains such as visual memory and learning and selective attention

Differential Regulation of the Variations Induced by Environmental Richness in Adult Neurogenesis as a Function of Time: A Dual Birthdating Analysis

Adult hippocampal neurogenesis (AHN) augments after environmental enrichment (EE) and it has been related to some of the anxiolytic, antidepressant and neuroprotective effects of EE. Indeed, it has been suggested that EE specifically modulates hippocampal neurogenic cell populations over the course of time. Here we have used dual-birthdating to study two subpopulations of newborn neuron in mice (Mus musculus): those born at the beginning and at the end of enrichment. In this way, we demonstrate that while short-term cell survival is upregulated after an initial 1 week period of enrichment in 2 month old female mice, after long-term enrichment (2 months) neither cell proliferation nor the survival of the younger newly born cell populations are distinguishable from that observed in non-enriched control mice. In addition, we show that the survival of older newborn neurons alone (i.e. those born at the beginning of the enrichment) is higher than in controls, due to the significantly lower levels of cell death. Indeed, these parameters are rapidly adjusted to the sudden cessation of the EE conditions. These findings suggest both an early selective, long-lasting effect of EE on the neurons born in the initial stages of enrichment, and a quick response when the environment again becomes impoverished. Therefore, EE induces differential effects on distinct subpopulations of newborn neurons depending on the age of the immature cells and on the duration of the EE itself. The interaction of these two parameters constitutes a new, specific regulation of these neurogenic populations that might account for the long-term enrichment's behavioral effects

Assessment of cognitive dysfunction in companion dogs.

Detection of cognitive dysfunction syndrome (CDS) in pet dogs is largely based on owner-reported alterations in behavior, providing only subjective data for diagnosis. The aim of this study was to validate standardized tests that permit the assessment of canine cognitive function in a clinical setting, possibly providing an objective method for diagnosing CDS. Privately owned dogs (N = 12, 5.9 \ub1 3.7 years) were administered a modified version of a neuropsychological test, originally validated on laboratory beagle dogs (Milgram et al., 1994). Learning rates, measured by the number of errors before achieving a learning criterion, were measured in two tasks of increasing cognitive demand. Simple discrimination learning was more readily acquired (9.57 \ub1 6.43 errors) than reversal learning (34.0 + 13.05; P<0.001). The same procedure in a sample of laboratory beagles (N = 7, 4.9 \ub1 2.2 years) produced a similar pattern; fewer errors were required to achieve discrimination than reversal (9.61 + 8.69 vs. 53.57 + 10.79; P < 0.001). Nonetheless, pet dogs outperformed beagles in reversal learning (P = 0.004). Only one owner reported behavioral abnormalities in his dog, which was also the oldest dog in the clinical population tested (16 years). This dog had the worst performance in reversal learning (65 errors), supporting the hypothesis that clinical based testing may be useful for diagnosis. In accordance with the theoretical framework of the model proposed by Milgram, the results confirm that objective neuropsychological tests can be used to assess cognitive functions in both laboratory and pet dogs. A larger sample, including an expanded number of aged dogs, will help determine the sensitivity of these tests to objectively assess age-related cognitive deficits

Validation of a cognitive test battery for cats.

We have described previously a battery of cognitive tests that permit us to objectively assess cognitive function in dogs; however, similar multi-domain tests are not available for cats. The aim of this study was to validate a test battery for cats modeled after those developed for dogs. The tasks were intended to assess a variety of cognitive domains, including learning ability, executive function, visuospatial learning and working memory. Kittens (N 5 16; 4.5 6 0.1 months) were tested on the following tasks: positional discrimination learning and reversal in a t-maze apparatus; object discrimination learning and reversal; and a delayed- non-matching-to-position task (DNMP). More errors were committed on the reversal phase of both the positional dis- crimination and object discrimination tests. Several of the cats also showed DNMP learning within the time-frame of the study. Cats committed more errors on both reversal tests compared to the respective learning test, which is con- sistent with the greater demands of this executive function test. Executive function is a high level cognitive ability that changes with development in rodents, dogs, non-human pri- mates and humans. This study demonstrates the feasibility of developing neuropsychological tests for cats that produce data consistent with that obtained in other species and that will be useful for examining cognitive changes that occur in feline development. Key words: cat; cognitive function; executive function; learning; memory; neuropsychological test batter

The effects of Novifit on cognitive function in aged beagle dogs.

Canine cognitive dysfunction syndrome (CDS) is a diag- nosis based on age-related behavioral changes likely related to alterations in brain function. In the laboratory, both age- and pathology-related changes in cognitive function can be identified using neuropsychological tests. The current study sought to evaluate the efficacy of NovifitÒ (S-Adenosyl-L- Methionine-Tosylate Disulfate), a novel supplement for the management of CDS, on improving cognitive function in laboratory dogs. Fourteen aged (9.2 to 12.8 years) Beagle dogs were assessed on tests of memory, executive function, and selective attention using the delayed non-matching to position task (DNMP), an object learning and reversal task (ODR), and a variable object discrimination test (VOD), respectively. The dogs were divided into placebo and treatment groups equivalent on baseline DNMP perfor- mance. No effect of treatment was found on the DNMP. On the ODR, the control group committed more errors on the reversal compared to the learning phase. By contrast, the increase in errors between the two phases was reduced in the treatment group, which suggested an enhancement of executive function. On the 2-choice subcomponent of the VOD, the placebo group showed reduced performance when the distracter object was changed. The treatment group showed an improvement consistent with improved executive function. The current study indicated Novifit may improve executive function, which was supported by the results of both the ODR and VOD. Overall, the results suggest that Novifit may be effective in CDS by improving a dog’s ability to cope with change. Key words: cognitive dysfunction syndrome; dog; laboratory model; learning; memory; supplemen