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jtitle_s:("Age (dorer)")
1.  Homer-1a immediate early gene expression correlates with better cognitive performance in aging 
Age  2012;35(5):1799-1808.
The molecular mechanisms underlying cognitive decline during healthy aging remain largely unknown. Utilizing aged wild-type C57BL/6 mice as a model for normal aging, we tested the hypothesis that cognitive performance, memory, and learning as assessed in established behavioral testing paradigms are correlated with the differential expression of isoforms of the Homer family of synaptic scaffolding proteins. Here we describe a loss of cognitive and motor function that occurs when Homer-1a/Vesl-1S protein levels drop during aging. Our data describe a novel mechanism of age-related synaptic changes contributing to loss of biological function, spatial learning, and memory formation as well as motor coordination, with the dominant negative uncoupler of synaptic protein clustering, Homer-1a/Vesl-1S, as a potential target for the prophylaxis and treatment of age-related cognitive decline.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9479-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3776093  PMID: 23054826
Behavior; Cognition; Cognitive aging; Learning; Memory; Synapse
2.  Coenzyme Q10 supplementation reverses age-related impairments in spatial learning and lowers protein oxidation 
Age  2012;35(5):1821-1834.
Coenzyme Q10 (CoQ) is widely available as a dietary supplement and remains under consideration as a treatment for age-associated neurodegenerative conditions. However, no studies have determined if supplementation, initiated relatively late in life, could have beneficial effects on mild functional impairments associated with normal brain aging. Accordingly, the current study assessed the effect of CoQ intake in older mice for which cognitive and psychomotor impairments were already evident. Separate groups of young (3.5 months) and relatively old mice (17.5 months) were fed a control diet or a diet supplemented with low (0.72 mg/g) or high (2.81 mg/g) concentrations of CoQ for 15 weeks. After 6 weeks, the mice were given tests for spatial learning (Morris water maze), spontaneous locomotor activity, motor coordination, and startle reflex. Age-related impairments in cognitive and psychomotor functions were evident in the 17.5-month-old mice fed the control diet, and the low-CoQ diet failed to affect any aspect of the impaired performance. However, in the Morris water maze test, old mice on the high-CoQ diet swam to the safe platform with greater efficiency than the mice on the control diet. The old mice supplemented with the high-CoQ diet did not show improvement when spatial performance was measured using probe trials and failed to show improvement in other tests of behavioral performance. Protein oxidative damage was decreased in the mitochondria from the heart, liver, and skeletal muscle of the high-CoQ-supplemented mice and, to some extent, in the brain mitochondria. Contrasting with the deleterious effect of long-term CoQ supplementation initiated during young adulthood previously published, this study suggests that CoQ improves spatial learning and attenuates oxidative damage when administered in relatively high doses and delayed until early senescence, after age-related declines have occurred. Thus, in individuals with age-associated symptoms of cognitive decline, high-CoQ intake may be beneficial.
PMCID: PMC3776107  PMID: 23138632
Aging; Coenzyme Q10; Ubiquinone; Ubidecarenone; C57BL/6J; Oxidative damage; Mitochondria
3.  Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia 
Age  2006;28(3):297-307.
Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer’s disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD.
PMCID: PMC3259150  PMID: 22253496
Alzheimer’s disease; hippocampus; ischemia; middle cerebral artery; stroke; vascular dementia
4.  Rodent models of brain aging and neurodegeneration 
Age  2006;28(3):219-220.
PMCID: PMC3259152
5.  Profiling psychomotor and cognitive aging in four-way cross mice 
Age  2006;28(3):265-282.
In part due to their genetic uniformity and stable characteristics, inbred rodents or their F1 progeny are frequently used to study brain aging. However, it is recognized that focus on a single genotype could lead to generalizations about brain aging that might not apply to the species as a whole, or to the human population. As a potential alternative to uniform genotypes, genetically heterogeneous (HET) mice, produced by a four-way cross, were tested in the current study to determine if they exhibit age-related declines in cognitive and psychomotor function similar to other rodent models of brain aging. Young (4 months) and older (23 months) CB6F1 × C3D2F1 mice were administered a variety of tests for cognitive, psychomotor, and sensory/reflexive capacities. Spontaneous locomotion, rearing, and ability to turn in an alley all decreased with age, as did behavioral measures sensitive to muscle strength, balance, and motor coordination. Although no effect of age was found for either startle response amplitude or reaction time to shock stimuli, the old mice reacted with less force to low intensity auditory stimuli. When tested on a spatial swim maze task, the old mice learned less efficiently, exhibited poorer retention after a 66-h delay, and demonstrated greater difficulty learning a new spatial location. In addition, the older mice were less able to learn the platform location when it was identified by a local visual cue. Because there was a significant correlation between spatial and cued discrimination performance in the old mice, it is possible that age-related spatial maze learning deficits could involve visual or motor impairments. Variation among individuals increased with age for most tests of psychomotor function, as well as for spatial swim performance, suggesting that four-way cross mice may be appropriate models of individualized brain aging. However, the analysis of spatial maze learning deficits in older CB6F1 × C3D2F1 mice may have limited applicability in the study of brain aging, because of a confounding with visually cued performance deficits.
PMCID: PMC3259154  PMID: 22253494
BALB/c; BCCD HET mice; brain aging; C3H; C57BL/6; CB6F1 × C3D2F1; DBA/2; psychomotor function; spatial memory; visual function
6.  Spatial learning and psychomotor performance of C57BL/6 mice: age sensitivity and reliability of individual differences 
Age  2006;28(3):235-253.
Two tests often used in aging research, the elevated path test and the Morris water maze test, were examined for their application to the study of brain aging in a large sample of C57BL/6JNia mice. Specifically, these studies assessed: (1) sensitivity to age and the degree of interrelatedness among different behavioral measures derived from these tests, (2) the effect of age on variation in the measurements, and (3) the reliability of individual differences in performance on the tests. Both tests detected age-related deficits in group performance that occurred independently of each other. However, analysis of data obtained on the Morris water maze test revealed three relatively independent components of cognitive performance. Performance in initial acquisition of spatial learning in the Morris maze was not highly correlated with performance during reversal learning (when mice were required to learn a new spatial location), whereas performance in both of those phases was independent of spatial performance assessed during a single probe trial administered at the end of acquisition training. Moreover, impaired performance during initial acquisition could be detected at an earlier age than impairments in reversal learning. There were modest but significant age-related increases in the variance of both elevated path test scores and in several measures of learning in the Morris maze test. Analysis of test scores of mice across repeated testing sessions confirmed reliability of the measurements obtained for cognitive and psychomotor function. Power calculations confirmed that there are sufficiently large age-related differences in elevated path test performance, relative to within age variability, to render this test useful for studies into the ability of an intervention to prevent or reverse age-related deficits in psychomotor performance. Power calculations indicated a need for larger sample sizes for detection of intervention effects on cognitive components of the Morris water maze test, at least when implemented at the ages tested in this study. Variability among old mice in both tests, including each of the various independent measures in the Morris maze, may be useful for elucidating the biological bases of different aspects of dysfunctional brain aging.
PMCID: PMC3259155  PMID: 22253492
brain aging; bridge walking; elevated path test; balance beam; inbred mice; individual differences; Morris maze; psychomotor function; spatial learning
7.  Lifelong vitamin E intake retards age-associated decline of spatial learning ability in apoE-deficient mice 
Age  2005;27(1):5-16.
The potential for lifelong vitamin E supplementation to delay age-associated cognitive decline was tested in apoE-deficient and wild-type C57BL/6 mice. Beginning at eight weeks of age, the mice were maintained on a control diet or diets supplemented with dl-α-tocopheryl acetate yielding approximate daily intakes of either 20 or 200 mg/kg body weight. When 6 or 18 months of age, cognitive functioning of the mice was assessed using swim maze and discriminated avoidance testing procedures. For the mice maintained on control diets, the age-related declines in swim maze performance were relatively larger in apoE-deficient mice when compared with wild-type. On the other hand, age-associated declines in learning and working memory for discriminated avoidance were similar in the two genotypes. The 200-mg/kg dose of vitamin E prevented the accelerated decline in spatial learning apparent in 18-month-old apoE-deficient mice, but had no equivalent effect on performance declines attributable to normal aging in the wild-type mice. Vitamin E supplementation failed to prevent age-related impairments in learning and memory for discriminated avoidance observed in both the wild-type and apoE-deficient mice. The current findings are consistent with the hypothesis that apoE deficiency confers an accelerated, though probably selective, loss of brain function with age. This loss of function would appear to involve pathogenic oxidative mechanisms that can be prevented or offset by antioxidant supplementation.
PMCID: PMC3456095  PMID: 23598599
alpha-Tocopherol; apolipoprotein E; apoE−/− mice; body weight; brain aging; C57BL/6 mice; cognitive decline; learning and memory; oxidative stress; spatial memory; survival; vitamin E; working memory

Results 1-7 (7)