Long-term visual object recognition memory in aged rats

Aging is associated with memory impairments, but the neural bases of this process need to be clarified. To this end, behavioral protocols for memory testing may be applied to aged animals to compare memory performances with functional and structural characteristics of specific brain regions. Visual object recognition memory can be investigated in the rat using a behavioral task based on its spontaneous preference for exploring novel rather than familiar objects. We found that a behavioral task able to elicit long-term visual object recognition memory in adult Long-Evans rats failed in aged (25-27 months old) Wistar rats. Since no tasks effective in aged rats are reported in the literature, we changed the experimental conditions to improve consolidation processes to assess whether this form of memory can still be maintained for long term at this age: the learning trials were performed in a smaller box, identical to the home cage, and the inter-trial delays were shortened. We observed a reduction in anxiety in this box (as indicated by the lower number of fecal boli produced during habituation), and we developed a learning protocol able to elicit a visual object recognition memory that was maintained after 24 h in these aged rats. When we applied the same protocol to adult rats, we obtained similar results. This experimental approach can be useful to study functional and structural changes associated with age-related memory impairments, and may help to identify new behavioral strategies and molecular targets that can be addressed to ameliorate memory performances during aging.     

Diphenyl diselenide-supplemented diet and swimming exercise enhance novel object recognition memory in old rats

The benefits of exercise and the element selenium on mental health and cognitive performance are well documented. The purpose of the present study was to investigate whether the intake of a diet supplemented with diphenyl diselenide [(PhSe)₂] and the swimming exercise could enhance memory in old Wistar rats. Male Wistar rats (24 months) were fed daily with standard diet chow or standard chow supplemented with 1 ppm of (PhSe)₂ during 4 weeks. Animals were submitted to swimming training with a workload (3 % of body weight, 20 min/day for 4 weeks). After 4 weeks, the object recognition test (ORT) and the object location test (OLT) were performed. The results of this study demonstrated that intake of a supplemented diet with (PhSe)₂ and swimming exercise was effective in improving short-term and long-term memory as well as spatial learning, increasing the hippocampal levels of phosphorylated cAMP-response element-binding protein (CREB) in old rats. This study also provided evidence that (PhSe)₂-supplemented diet facilitated memory of old rats by modulating cAMP levels and stimulating CREB phosphorylation, without altering the levels of Akt.     

Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics

Oxidative stress has been implicated in cognitive impairment in both old experimental animals and aged humans. This implication has led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. In particular, increase in protein oxidation was completely prevented, whereas increase in lipid peroxidation was decreased by approximately 50%. In addition, we observed a significant negative correlation between contextual fear learning and levels of protein oxidation in brain. These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species.     

Plastic modifications induced by object recognition memory processing

Long-term potentiation (LTP) phenomenon is widely accepted as a cellular model of memory consolidation. Object recognition (OR) is a particularly useful way of studying declarative memory in rodents because it makes use of their innate preference for novel over familiar objects. In this study, mice had electrodes implanted in the hippocampal Schaffer collaterals–pyramidal CA1 pathway and were trained for OR. Field EPSPs evoked at the CA3-CA1 synapse were recorded at the moment of training and at different times thereafter. LTP-like synaptic enhancement was found 6 h posttraining. A testing session was conducted 24 h after training, in the presence of one familiar and one novel object. Hippocampal synaptic facilitation was observed during exploration of familiar and novel objects. A short depotentiation period was observed early after the test and was followed by a later phase of synaptic efficacy enhancement. Here, we show that OR memory consolidation is accompanied by transient potentiation in the hippocampal CA3-CA1 synapses, while reconsolidation of this memory requires a short-lasting phase of depotentiation that could account for its well described vulnerability. The late synaptic enhancement phase, on the other hand, would be a consequence of memory restabilization.     

Reversal of age-associated memory impairment by rosuvastatin in rats

Increased levels of iron in brain regions have been reported in neurodegenerative disorders as well as in normal brain aging. We have previously demonstrated that neonatal iron loading induces cognitive impairment in adult rats. Here, we evaluate the effects of neonatal iron treatment on cognition in aged rats. We also investigated the effects of a late subchronic rosuvastatin treatment on iron- and age-induced cognitive deficits. Rats received vehicle or 10.0 mg/kg Fe²⁺ orally at postnatal days 12–14. When animals reached the age of 23 months, they received daily intraperitoneal injections of saline or rosuvastatin (0.2 or 2.0 mg/kg) for 21 days. Twenty-four hours after the last injection, they were submitted to novel object recognition training. Retention test sessions were performed 1.5 and 24 h after training, in order to assess short-term and long-term memory, respectively. Results indicated that aged animals that received iron in the neonatal period showed more severe memory deficits than vehicle-treated ones, suggesting that iron potentiates age-associated memory impairments. Rosuvastatin improved recognition memory deficits associated with iron loading and aging, providing evidence that statins may be considered for the treatment of age-associated cognitive decline.     

The effects of presentation rate and encoding task on age-related memory deficits

Young and old adults studied several lists of words at each of three presentation durations (1.5, 3, and 6 s/word). Under standard, intentional learning instructions the magnitude of the age-related recall deficit increased with longer presentation durations. When a semantic orienting question was used to guide the encoding of the items on each list, however, an equivalent benefit of longer study times was observed for the two age groups. In delayed recognition testing, the age groups also showed equivalent benefits from longer study times. These results were interpreted within the context of a processing deficit framework of age differences in memory, in which age differences are due to differences in the spontaneous use of organizational strategies. The results are not well described by a cognitive slowing account of age differences in memory.     

Reversal of age-related neural timing delays with training

Neural slowing is commonly noted in older adults, with consequences for sensory, motor, and cognitive domains. One of the deleterious effects of neural slowing is impairment of temporal resolution; older adults, therefore, have reduced ability to process the rapid events that characterize speech, especially in noisy environments. Although hearing aids provide increased audibility, they cannot compensate for deficits in auditory temporal processing. Auditory training may provide a strategy to address these deficits. To that end, we evaluated the effects of auditory-based cognitive training on the temporal precision of subcortical processing of speech in noise. After training, older adults exhibited faster neural timing and experienced gains in memory, speed of processing, and speech-in-noise perception, whereas a matched control group showed no changes. Training was also associated with decreased variability of brainstem response peaks, suggesting a decrease in temporal jitter in response to a speech signal. These results demonstrate that auditory-based cognitive training can partially restore age-related deficits in temporal processing in the brain; this plasticity in turn promotes better cognitive and perceptual skills.     

Glucocorticoid effects on object recognition memory require training-associated emotional arousal

Considerable evidence implicates glucocorticoid hormones in the regulation of memory consolidation and memory retrieval. The present experiments investigated whether the influence of these hormones on memory depends on the level of emotional arousal induced by the training experience. We investigated this issue in male Sprague-Dawley rats by examining the effects of immediate posttraining systemic injections of the glucocorticoid corticosterone on object recognition memory under two conditions that differed in their training-associated emotional arousal. In rats that were not previously habituated to the experimental context, corticosterone (0.3, 1.0, or 3.0 mg/kg, s.c.) administered immediately after a 3-min training trial enhanced 24-hr retention performance in an inverted-U shaped dose-response relationship. In contrast, corticosterone did not affect 24-hr retention of rats that received extensive prior habituation to the experimental context and, thus, had decreased novelty-induced emotional arousal during training. Additionally, immediate posttraining administration of corticosterone to nonhabituated rats, in doses that enhanced 24-hr retention, impaired object recognition performance at a 1-hr retention interval whereas corticosterone administered after training to well-habituated rats did not impair 1-hr retention. Thus, the present findings suggest that training-induced emotional arousal may be essential for glucocorticoid effects on object recognition memory.     

Chronic [D-Ala2]-growth hormone-releasing hormone administration attenuates age-related deficits in spatial memory

The age-related decline in growth hormone is one of the most robust endocrine markers of biological aging and has been hypothesized to contribute to the physiological deficits observed in aged animals. However, there have been few studies of the impact of this hormonal decline on brain aging. In this study, the effect of long-term subcutaneous administration of [D-Ala2]-growth hormone-releasing hormone (GHRH) on one measure of brain function, memory, was investigated. Animals were injected daily with 2.3 microg of [D-Ala2]-GHRH or saline from 9 to 30 months of age, and the spatial learning and reference memory of animals were assessed by using the Morris water maze and compared with those of 6-month-old animals. Results indicated that spatial memory decreased with age and that chronic [D-Ala2]-GHRH prevented this age-related decrement (24% improvement in the annulus-40 time and 23% improvement in the number of platform crossings compared with saline treated, age-matched controls; p < .05 each). No changes were noted in sensorimotor performance. [D-Ala2]-GHRH attenuated the age-related decline in plasma concentrations of insulinlike growth factor-1 (IGF-1) (p <.05). These data suggest that growth hormone and IGF-1 have important effects on brain function, that the decline in growth hormone and IGF-1 with age contributes to impairments in reference memory, and that these changes can be reversed by the chronic administration of GHRH.     

Cognitive impairment in old rats: a comparison of object displacement, object recognition and water maze

The behavioral performance of young and aged rats was studied in a repeated-trials test. Young animals reacted to both spatial displacement and novelty, whereas most aged rats lost the ability to react to novelty although maintaining spatial memory. The cluster analysis procedure performed on all the tested subjects enabled the recognition of a consistent group of the aged sample (35%) with a mild degree of spatial and non-spatial memory impairment. Spatial memory impairment of some of the aged animals was also evaluated in the Morris water maze test. On the fifth day of the task, we observed a very low percentage of impaired aged animals, which partially corresponded to the impaired group identified by the object recognition test. In contrast, the subgroup of mildly impaired rats performed similarly to the young animals. We advance that the Morris water maze might represent a stressful experimental condition for aged rats, enhancing the motivational level of animals subjected to this procedure. This condition may alter the cognitive responses. As a consequence, the "mildly impaired" rats, which may be considered an interesting group for investigating memory-enhancing drugs, will infrequently be recognized with the Morris water maze test. Cognitive impairment in aged rats should be studied utilizing a sensitive test in which motivation does not substantially influence the results of the test.     

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.     

Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats

Inhibition of phosphodiesterase-4 (PDE4) by rolipram, a prototypical PDE4 inhibitor, reverses memory impairment produced pharmacologically or genetically. Comparably, much less is known about the effect of rolipram on cerebral ischemia-induced memory deficits. The objective of this study was to determine the effects of rolipram on ischemia-induced memory deficit, neuronal damage, and alteration of PDE4 activity in the hippocampus. Memory was examined using Morris water-maze and step-through passive avoidance tests in rats subjected to global cerebral ischemia with or without repeated treatment with rolipram (0.3 or 1 mg/kg, i.p.); neuronal damage in the hippocampus and PDE4 activity in hippocampal tissues were determined using Nissl staining and HPLC, respectively. In the water-maze test, cerebral ischemia significantly increased the escape latency to reach the platform during acquisition training and decreased the exploration time in the target quadrant in the probe trial test; these were blocked by rolipram in a dose-dependent manner. Rolipram also reduced the distracted platform searches induced by cerebral ischemia. In the passive avoidance test, ischemia decreased the 24-h latency to the dark compartment, which was also blocked by rolipram treatment. In addition, Nissl staining revealed ischemia-induced neuron loss in hippocampal CA1; this was blocked by rolipram. Further, cerebral ischemia led to increases in activity of PDE, primarily PDE4, in the hippocampus, which also was antagonized by rolipram. These results suggest that rolipram prevents cerebral ischemia-induced memory deficits via inhibition of increased PDE4 activity and attenuation of hippocampal, neuronal damages induced by ischemia. PDE4 may be a target for treatment of cognitive disorders associated with cerebral ischemia.     

Effect of coenzyme Q10 supplementation on diabetes induced memory deficits in rats

Metabolic Brain Disease - The main objective of current work was to determine the effects of low and high dose supplementation with coenzyme Q10 (CoQ10) on spatial learning and memory in rats with...     

Poor blood glucose regulation predicts sleep and memory deficits in normal aged rats

Poor glucose regulation predicts memory deficits in individual elderly humans. The present experiment determined whether glucose regulation was also related to memory and to sleep in aged rodents. Glucose regulation, inhibitory avoidance, and daytime sleep were assessed in young (3-month-old) and old (24-month-old) rats. Correlations were obtained between glucose regulation and the other variables in individual rats. In old rats, the magnitude of increases in blood glucose levels after glucose injections (500 mg/kg) was inversely correlated with retention of inhibitory avoidance and duration of paradoxical sleep bouts. In young rats, these measures were not significantly correlated. Because the deficits in sleep and memory in aged rats were largely confined to those rats with poor glucose control, peripheral glucose regulation may be a useful biological marker that accompanies cognitive and neurobiological dysfunction during aging.     

Reversing age-related decline in working memory

Higher cognitive functions, such as working memory and the ability to focus attention, decline as people age. Recently, it has been reported that decline in working memory in aging rhesus monkeys correlates with the loss of activity of a specific set of neurons in the prefrontal cortex during a delay following a learning cue. The activity of these neurons can be rescued by stimulating α-2 adrenergic receptors, inhibiting cyclic adenosine monophosphate (cAMP) signaling, or closing potassium channels that are known to inhibit firing and synaptic connectivity. Agents that stimulate neurons expressing α-2 adrenergic receptors may prove useful in treating working memory loss in humans.     

Reversal of age-related effects in rat muscle phosphoglycerate kinase.

Rat muscle phosphoglycerate kinase is one of several enzymes in which age-related effects have been identified. Thus, samples of this enzyme isolated from old rats display a greatly increased heat stability as compared with enzyme isolated from young animals. Previous studies detected no differences in the sequence of amino acids or in the net charge between the young and old forms of the enzyme and it was concluded that the age-related structural modifications are purely conformational. The present study was conducted with the aim of critically testing this hypothesis. To this end, samples of phosphoglycerate kinase purified from skeletal muscle of young and old rats were unfolded by an 18-hr incubation in a 2 M guanidine hydrochloride solution at 4 degrees C, a treatment that results in extensive loss of the three-dimensional structure of the enzyme. A complete reactivation of both enzymes was achieved by dilution of the unfolded enzyme solutions into a large excess of denaturant-free buffer followed by 4 hr of incubation at 25 degrees C. The reactivation kinetics of the unfolded young and old enzymes were practically identical and the refolded products, compared using heat-inactivation kinetics as a sensitive probe, were found to be identical. Moreover, their heat inactivation coincided with that of young untreated phosphoglycerate kinase. These results demonstrate the reversibility of age-related effects at the molecular level and provide strong support for the hypothesis that the modifications in phosphoglycerate kinase in old muscle are purely conformational and, hence, clearly postsynthetic.     

Pretreatment with crocin along with treadmill exercise ameliorates motor and memory deficits in hemiparkinsonian rats by anti-inflammatory and antioxidant mechanisms

The motor symptoms of Parkinson’s disease (PD) are preceded by non-motorized symptoms including memory deficits. Treatment with dopamine replacement medications, such as L-DOPA only control motor symptoms and does not meet the clinical challenges of the disease, such as dyskinesia, non-motor symptoms, and neuroprotection. The purpose of the current study was to examine the neuroprotective potential of crocin and physical exercise in an animal model of PD. Male Wistar rats ran on a horizontal treadmill and/or pretreated with crocin at a dose of 100 mg/kg. Then, 16 μg of the neurotoxin 6-hydroxydopamine (6-OHDA) was microinjected into left medial forebrain bundle. Crocin treatment and/or exercise continued for 6 more weeks. Spatial and aversive memories, rotational behaviour, inflammatory and oxidative stress parameters were assessed at the end of week 6 post surgery. The results showed that pretreatment with crocin alone and in combination with exercise decreased the total number of rotaions as compared with 6-OHDA-lesioned group. Furthermore, treatment of parkinsonian rats with crocin along with exercise training improved aversive and spatial memories. Biochemical analysis showed that crocin and exercise (alone and in combination) reduced tumor necrosis factor- (TNF) α levels in the striatum. Moreover, treatment with crocin at a dose of 100 mg/kg decreased the lipid peroxidation levels in the hippocampus, while exercise training increased the total thiol concentration. In conclusion, our findings indicated that pretreatment with crocin along with treadmill exercise ameliorated motor and memory deficits induced by 6-OHDA, which is considered to be due to their antioxidant and anti-inflammatory activities. The results suggest that combined therapy with crocin and exercise may be protective for motor and memory deficits in PD patients.

     

Learning and memory deficits in rats induced by chronic thinner exposure are reversed by melatonin

Thinner is a neurotoxic mixture which is widely used as an aromatic industrial solvent. This product has been shown to cause functional and structural changes in the central nervous system. We investigated the effect of exposure to high concentrations (3000 p.p.m.) of thinner for 45 days (1 hr/day) on cognitive functions and the levels of neural cell adhesion molecules (NCAM) and lipid peroxidation products (LPO) in the hippocampus, cortex and cerebellum of rats. The actions of melatonin on the effects produced by thinner exposure were also tested. Thinner exposure caused a significant increase in LPO (malondialdehyde and 4-hydroxyalkenals) in all brain regions. Melatonin administration significantly reduced LPO and elevated glutathione levels in the brain regions. NCAM (180 kDa) was significantly decreased in hippocampus and cortex of thinner-exposed rats. Furthermore, thinner-exposed rats showed cognitive deficits in passive avoidance and Morris water maze tasks, whereas in the rats chronically treated with melatonin these effects were reversed. This study indicates that treatment with melatonin prevents learning and memory deficits caused by thinner exposure possibly by reducing oxidative stress and regulating neural plasticity.