Learning Ability In Aged Rats Research Articles

N-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acid-derived docosanoids in aged rats

We investigated whether a highly purified eicosapentaenoic acid (EPA) and a concentrated n-3 fatty acid formulation (prescription TAK-085) containing EPA and docosahexaenoic acid (DHA) ethyl ester could improve the learning ability of aged rats and whether this specific outcome had any relation with the brain levels of EPA-derived eicosanoids and DHA-derived docosanoids. The rats were tested for reference memory errors (RMEs) and working memory errors (WMEs) in an eight-arm radial maze. Fatty acid compositions were analyzed by GC, whereas brain eicosanoid/docosanoids were measured by LC–ESI-MS–MS-based analysis. The levels of lipid peroxides (LPOs) were measured by thiobarbituric acid reactive substances. The administration of TAK-085 at 300mg·kg−1day−1 for 17weeks reduced the number of RMEs in aged rats compared with that in the control rats. Both TAK-085 and EPA administration increased plasma EPA and DHA levels in aged rats, with concurrent increases in DHA and decreases in arachidonic acid in the corticohippocampal brain tissues. TAK-085 administration significantly increased the formation of EPA-derived 5-HETE and DHA-derived 7-, 10-, and 17-HDoHE, PD1, RvD1, and RvD2. ARA-derived PGE2, PGD2, and PGF2α significantly decreased in TAK-085-treated rats. DHA-derived mediators demonstrated a significantly negative correlation with the number of RMEs, whereas EPA-derived mediators did not exhibit any relationship. Furthermore, compared with the control rats, the levels of LPO in the plasma, cerebral cortex, and hippocampus were significantly reduced in TAK-085-treated rats. The findings of the present study suggest that long-term EPA+DHA administration may be a possible preventative strategy against age-related cognitive decline.

A decreased survival of proliferated cells in the hippocampus is associated with a decline in spatial memory in aged rats

In aged rats, although learning and memory impairment is prominent, both the number of granular cells and the degree of neuronal progenitor proliferation in the hippocampus are known to be preserved. We examined the association between the survival of newly generated neurons in the hippocampus and the learning ability in aged rats. By using BrdU, a cell proliferation marker to determine neurogenesis and contextual fear conditioning to determine learning ability, we found that in aged rats, along with memory impairment, the survival of both the proliferated cells at baseline and those enhanced by contextual fear conditioning decreased remarkably. These results suggest that the integration of newly generated neurons into hippocampal circuitry is decreased with aging, this phenomenon may, in part, explain the decline in learning and memory in aged rats.

The Slow Afterhyperpolarization in Hippocampal CA1 Neurons Covaries with Spatial Learning Ability in Aged Fisher 344 Rats

Rodents commonly exhibit age-related impairments in spatial learning tasks, deficits widely thought to reflect cellular or synaptic dysfunction in the hippocampus. Using whole-cell recordings, we examined the afterhyperpolarization (AHP) in CA1 pyramidal cells in hippocampal slices from young (4-6 months of age) and aged (24-26 months of age) Fisher 344 male rats that had been behaviorally characterized in the Morris water maze. The slow AHP (sAHP) recorded from learning-impaired aged rats (AI) was significantly larger than that seen in either age-matched unimpaired rats or young controls. Among aged rats, sAHP amplitude was inversely correlated with both acquisition and probe performance in the water maze. Action potential parameters among the three groups were similar, except for spike accommodation, which was more pronounced in the AI group. Intracellular application of the cAMP analog 8-CPT-cAMP suppressed the sAHP but failed to reveal any age- or performance-related differences in the medium AHP. 8-CPT-cAMP abolished the age-related difference in spike accommodation, whereas instantaneous firing frequency was unchanged. Calcium spikes were of similar amplitude in all three groups but were broader and had significantly larger tails in aged rats; these age-related changes could be mimicked in young neurons after exposure to BayK8644. The calcium spike among aged rats correlated with task acquisition in the maze but, unlike the sAHP, failed to correlate with probe performance. This is the first demonstration that sAHP amplitude covaries with spatial learning ability in aged rats, implying that CA1 excitability strongly influences certain aspects of cognitive function. Our findings also indicate that multiple processes, in addition to elevated calcium influx, conspire to induce cognitive decline during aging.

The effect of l-carnitine on T-maze learning ability in aged rats

l-carnitine is of considerable interest because of its capacity to counteract several physiological and pathological phenomena typical of brain aging processes. We examined the effects of l-carnitine on the learning ability of old rats. 100 mg/kg per body weight per day l-carnitine was administered orally to old (21 months) male Sprague–Dawley rats (OLD-CAR) for a period of 2 months. Old (21 months, OLD-CO) and young (7 months, YG-CO) control animals received tap water exclusively. Performance of the OLD-CAR and OLD-CO was compared with that of YG-CO in a multiple T-maze. The mean run time values showed a significant ( P=0.01) difference of the OLD-CAR rats to the OLD-CO but no significant differences between OLD-CAR and YG-CO. For the T-maze parameter mean correct responses we were able to demonstrate that l-carnitine treated old rats made significantly ( P=0.03) less errors and significantly ( P=0.01) more animals reached the T-maze goal compared with OLD-CO but no significant differences were observed between OLD-CAR and YG-CO. The results of the present study clearly demonstrate that carnitine treatment improves the learning ability of old rats and seems to be able to reduce the loss of cognitive functions that occur with aging.

Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats.

1. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on spatial memory related learning ability in aged (100 weeks) male Wistar rats. 2. Rats were fed a fish oil-deficient diet through three generations and were then randomly divided into two groups. Over 10 weeks, one group was per orally administered 300 mg/kg per day DHA dissolved in 5% gum Arabic solution and the other group was administered the vehicle alone. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to estimate two types of spatial memory related learning ability displayed by reference memory error and working memory error. 3. Chronic administration of DHA significantly decreased the number of reference memory errors and working memory errors. 4. The level of lipid peroxide (LPO) in the hippocampus tended to decrease with chronic DHA administration and demonstrated a positive correlation with the number of reference memory errors. 5. These results suggest that the accumulation of hippocampal LPO reduces spatial memory related learning ability in aged rats. Moreover, chronic administration of DHA was effective in decreasing the level of hippocampal LPO, then improving learning ability.

Spatial memory and NGF levels in aged rats: natural variability and effects of acetyl-L-carnitine treatment.

The natural variability of behavioral performance of aged rats was used to evaluate the effect of acetyl-L-carnitine (ALCAR) on spatial learning and NGF levels in different brain areas. We used a cluster analysis procedure to subdivide the aged animals into three classes of performance (good, intermediate, and poor). These three classes were equally subdivided into controls and ALCAR-treated animals in order to investigate its effect on spatial retention. The stratification of animals prior to treatment allowed us to highlight the state dependency of the action of ALCAR. The effect of the molecule in improving spatial retention was evident only in the intermediate performance group. Furthermore, the drug reduced the NGF levels in the basal forebrain of treated animals, especially in the intermediate performance group. These results suggest a performance-dependent effect of ALCAR and a nonlinear relationship between NGF levels and learning ability in aged rats.

Hippocampal nerve growth factor levels are related to spatial learning ability in aged rats

Brain nerve growth factor (NGF) was determined in two groups of aged rats: 'good' and 'poor' performers. The animals were selected out of a population of 40 aged rats (26-28 months old) trained in a spatial learning task. Animals performing well in the test had significantly higher NGF in the hippocampus when compared to 'poor' performers. No differences in the levels of NGF were found in the cortex, septum and cerebellum. The results implicate hippocampal NGF in cognitive functioning of aged rats, and suggests that the forebrain cholinergic neuronal atrophy which has been observed in cognitively impaired aged rats may be due to reduced availability of target-derived NGF.

Effects of a high-linoleate and a high-alpha-linolenate diet on the learning ability of aged rats. Evidence against an autoxidation-related lipid peroxide theory of aging.

This study examined the effect of dietary alpha-linolenate (18:3n-3)/linoleate (18:2n-6) balance on brain lipid compositions and brightness-discrimination learning ability in aged rats. An alpha-linolenate-rich diet with a peroxidizability index (PI) of 142 and a linoleate-rich diet with a PI value of 80 were used. Long-term feeding of these diets induced a significant difference in the n-3/n-6 ratios of highly unsaturated fatty acids in brain, but the PI values and the conjugated diene contents were similar between the two dietary groups. Rats fed the alpha-linolenate-rich diet had a longer mean survival time and an increased learning ability in senescence. These results contradict an autoxidation-related lipid peroxide theory of aging, and indicate that the aging process must also be considered in terms of n-3/n-6 balance of dietary fats.